CN103224556B - Huntingdon disease (HD)-targeted proteins and their coding genes and use - Google Patents
Huntingdon disease (HD)-targeted proteins and their coding genes and use Download PDFInfo
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Abstract
The invention relates to the field of gene engineering and especially relates to Huntingdon disease (HD)-targeted proteins and their coding genes and use. The HD-targeted genes provided by the invention comprise Ctrl, ATP7A and ATP7B, and through gene silencing interference of Ctrl or overexpression of ATP7A and ATP7B, HD patient symptoms are obviously relieved or HD occurrence is delayed. According to the invention, the human HD-targeted proteins have amino acid sequences shown in the formulas of SEQ ID No.5, SEQ ID No.6, SEQ ID No.7, SEQ ID No.8 and SEQ ID No.9. The genes have nucleotide sequences shown in the formulas of SEQ ID No.10, SEQ ID No.11, SEQ ID No.12, SEQ ID No.13 and SEQ ID No.14. Through gene silencing or gene overexpression, the targeted genes can be used for improving HD patient athletic ability, prolonging a HD patient life, and relieving or preventing cut huntingtin (htt) deposition in the brain and htt deposition-caused nerve degeneration. The invention provides a novel treatment approach and key target positions for HD.
Description
Technical field
The present invention relates to genetically engineered field, concrete, the present invention relates to the target position albumen of a kind of Huntington chorea (Huntingdon Disease, HD) and encoding gene thereof and application.
Background technology
Huntington chorea (Huntingdon Disease, HD) is also called huntington chorea, is one of major nerve degenerative disease affecting human health at present.This is a kind of Delayed onset nervus retrogression inherited disease, be mainly in the elderly, occasionally in Children and teenager, men and women all can fall ill, incidence of occult, increases the weight of in slow Progressive symmetric erythrokeratodermia, and clinical realization is " three levy ", comprise dancing sample involuntary action, mental disorder and progressive dementia, mean survival time (MST) is 10-20.Because this disease is many in middle aged sequela, and there is no effective methods for the treatment of, progression of disease of can only leaving, finally lethal.Therefore, it is called as " quiet killer ", brings great misery to other members in sufferers themselves and family.At present, the mankind also do not treat the effective measure of this disease.
This disease is found already, but until 1872 have just carried out comprehensive and systematic description to it first by George Huntington.Huntington points out that it has hereditary property, and this disease is then with his naming.1993, HD cooperating research group exon amplification and cDNA clone technology, HD gene cowpea one J5 is positioned karyomit(e) 4p16.3, confirms to suddenly change as CAG Trinucleotide repeats on a J5 gene extron 1 patient simultaneously, now confirmed that CAG repeats sudden change and HD can be caused to occur.CAG tumor-necrosis factor glycoproteins on HD gene is encoded one section of poly glumine sequence (Polyglutamine, Po1yQ), and the PolyQ length of normal people is less than 35, and the PolyQ length of patient is then more than 36.The individual external aobvious situation to different size CAG tumor-necrosis factor glycoproteins such as BrinkImn is carried out research and is found, the penetrance of HD depends on the repetition number of CAG.Grah etc. find that homozygote patient HD falls ill comparatively early and symptom is more serious, and the length of CAG and age of onset are negative correlation.
The accumulation of htt albumen in brain containing the polyQ extended is considered to the major cause of bringing out HD.Restriction endonuclease cutting produces the htt albumen that N holds brachymemma, and is polymerized to oligomer and polymeric form in brain inner product, produces neurotoxicity.Although achieved to the research of HD the progress attracted people's attention, at present for the ununified conclusion of mechanism of causing a disease of HD, be which type of reason causes gathering of htt albumen actually, still unclear at present.
Increasing evidence shows, endogenic cation equilibrium is disorderly, and especially the concentration abnormality of iron and copper and the pathologic process of HD have very strong contacting.There are some researches show that patient's HD brain iron ion and copper ion concentration raise, have report to point out, when in vitro, cupric ion can cause htt exon1 polyQ protein aggregation, and the mouse htt albumen of extraction and copper have keying action.Therefore, by regulation and control cupric ion in IC accumulation, likely prevent or improve the development of HD illness.
Although identified the albumen participating in cupric ion transport in human brain to include Ctr1, Atox1, CCS, ScoI/II, ATP7A, ATP7B, in the cell that human brain is different the distribution situation of cupric ion and the regulation and control situation of cupric ion balance also not clear at present.
Although some experiment in vitro characterizes cupric ion may may have certain relation with the morbidity of HD, never more careful, in convictive body, evidence proves.Therefore, a kind of protein and the gene order necessity very thereof that can treat HD is provided.
Summary of the invention
Fruit bat is an extraordinary model of research human nerve's degenerative disease, so can be the effect of model animals research cupric ion in HD pathogenic process with fruit bat, the application of Huntington chorea be treated in research cupric ion translocator (Ctr1, ATP7A and ATP7B).Express at fruit bat brain the cardinal symptom that htt exon1 polyQ can reappear mankind HD, comprise surviving rate decline, dyskinesia, htt protein aggregation, nerve degeneration and the lost of life etc.By RNAi gene silent technology and process LAN technology, the fruit bat homologous gene of the present invention selective silence Ctr1B (the fruit bat homologous gene of mankind Ctr1) gene or the selectivity process LAN dmATP7(mankind ATP7A and ATP7B in HD fruit bat brain) gene significantly delayed the process of fruit bat HD illness, and selective silence ATP7 gene has increased the weight of the process of this illness.The present invention effectively treats HD illness to provide two crucial gene target position, is expected to the expression defence by regulating and controlling this gene target position and delays mankind HD disease.
According to the aminoacid sequence of the HD transgenic drosophila model target position PROTEIN C tr1B of the mankind of the present invention as shown in SEQ ID No.1
MDHGSDDSTSTAKSCPMIMVFHAGHCERILWRGWVASTVTEFVLSALAIFLVSFLYEALK 60
FLRQQLARREARRASEQLAAEQRRKNEAPAAGGCCSEAPLAEPREQTYWQRLFASSHIVQ 120
SLLNLLQIVISYLLMLIFMTFNYWLCLAVILGLGLGYFFFGWNKKNPDESECCP 175
The aminoacid sequence of the HD transgenic drosophila model target position albumen dmATP7 of the mankind is as shown in SEQ ID No.2
MPSDERVEATMSTVRLPIVGMTCQSCVRNITEHIGQKSGILGVRVILEENAGYFDYDPRQ 60
TDPARIASDIDDMGFECSYPGDAADPPETPASAWTNIRVVGMTCQSCVRNIEGNIGTKPG 120
IHSIEVQLAAKNARVQYDPAQYDPAQIAELIDDMGFEASVQEPRSPSQSPSPAPASSPKK 180
RATPTPPPPSYAQNGSAVAIPVEQELLTKCFLHIRGMTCASCVAAIEKHCKKIYGLDSIL 240
VALLAAKAEVKFNANVVTAENIAKSITELGFPTELIDEPDNGEAEVELEIMGMTCASCVN 300
KIESHVLKIRGVTTASVTLLTKRGKFRYITEETGPRSICEAIEALGFEAKLMTGRDKMAH 360
NYLEHKEEIRKWRNAFLVSLIFGGPCMVAMIYFMLEMSDKGHANMCCLVPGLSMENLVMF 420
LLSTPVQFFGGFHFYVQSYRAIKHGTTNMDVLISMVTTISYVYSVAVVIAAVLLEQNSSP 480
LTFFDTPPMLLIFISLGRWLEHIAKGKTSEALSKLLSLKAADALLVEISPDFDIISEKVI 540
SVDYVQRGDILKVIPGAKVPVDGKVLYGHSSCDESLITGESMPVAKRKGSVVIGGSINQN 600
GVLLVEATHTGENTTLAQIVRLVEEAQTSKAPIQQLADRIAGYFVPFVVVVSSITLIAWI 660
IIGFSNPNLVPVAMEHKMHMDQNTIIVSYAFKCALSVLAIACPCALGLATPTAVMVATGT 720
GAINGVLVKGATALENAHKVKTVVFDKTGTITHGTPMTSKVTLFVTAQVCSLARALTIVG 780
AAEQNSEHPIASAIVHFAKDMLNVGATPQAGSFGKSSHFQAVPGCGIRVTVSNYEQTLRQ 840
ACNADRIINYENLHRTHPQGSVPVDNGASIEHLLPQRSVRKSMELNNQQLLSDLVLEPEE 900
ELLTDQKIIDSPEILVLIGNREWMERNAIEVPLEISDCMTHEERKGHTAVLCALNGQLVC 960
MFAVSDMVKPEAHLAVYTLKRMGIDVVLLTGDNKNTAASIAREVGIRTVYAEVLPSHKVA 1020
KIQRIQANGIRVAMVGDGVNDSPALAQADVGITIAAGTDVAAEASDIVLMRNDLLDVVAC 1080
LDLSRCTVRRIRYNFFFASMYNLLGIPLASGLFAPYGFTLLPWMASVAMAASSVSVVCSS 1140
LLLKMYRKPTAKTLRTAEYEAQLAAERASGSEDELDKLSLHRGLDDLPEKGRMPFKRSST 1200
SLISRIFMHDYGNITSPDAKYGEGLLDPEEQYDGRTKIVRSRFHANDSTELQKL 1254
According to the transgenic drosophila model Target genes Ctr1B for the treatment of HD illness of the present invention, its above-mentioned Ctr1B albumen of encoding, such as, its nucleotide sequence is as shown in SEQ ID No.3.
atggatcacggctcggatgacagcaccagcacggccaagtcctgccctatgatcatggtg 60
ttccacgctggacactgcgagcgaattttgtggcgcggatgggtggcgtccactgtgacg 120
gagttcgtgctctccgccctggccatcttcctggtgtccttcctgtatgaggcgctcaag 180
ttcctgcgacagcaactggcgcgcagggaagcccgtcgagcaagcgagcagctggcggcg 240
gagcagcgtaggaagaacgaggctccggcagccggaggatgctgctcggaagctcccctg 300
gcggagccgagggagcagacctactggcagcgcttgttcgcctcgtcgcacatcgtccag 360
tccctgctgaacctgctgcagatcgtcatctcgtacctgctgatgctgatcttcatgacc 420
ttcaactactggctgtgcctggcagtgatcctgggactgggtctgggctacttcttcttc 480
ggctggaacaagaagaatcccgacgagagcgagtgctgtccttag 525
According to the transgenic drosophila model Target genes dmATP7 for the treatment of HD illness of the present invention, its above-mentioned dmATP7 albumen of encoding, such as, its nucleotide sequence is as shown in SEQ ID No.4.
atgccaagtgacgagagagtagaagcgacgatgtccacggtgcgcctgcccattgtgggc 60
atgacttgccagtcgtgtgtgcgcaatatcacagagcacattggccagaaatcgggaatc 120
cttggcgtgcgcgtcattctcgaggagaatgcgggctatttcgactacgatccccgacag 180
acggatcccgcccggatagccagcgatatcgacgacatgggcttcgagtgcagctatcca 240
ggggatgcagcagatcctcccgaaactcccgccagcgcatggaccaacatacgggtggtg 300
ggcatgacctgccagtcgtgcgtgcgcaacatcgaaggcaatatcggcaccaagccgggc 360
atccattccattgaggtgcaactggcggccaagaatgcccgcgttcagtacgatcccgcc 420
cagtatgatcccgcccagatagccgagctcatcgatgacatgggttttgaggctagtgtg 480
caggaacctcgatcgccatcccaatcgccgtcgcccgcccccgcctcatcacccaaaaag 540
agggcaactcctactcctccacctccttcatatgctcaaaatggttcggcagtggccata 600
cccgtcgaacaggagctactgaccaaatgctttctgcacatccgaggcatgacgtgcgcc 660
agctgtgtggccgccatcgagaagcactgcaagaagatctacggcctggacagcatcctg 720
gtagccctgctggccgccaaggcggaggtcaagttcaatgccaatgttgtgacggccgag 780
aatatagcgaaatcaatcacggagctgggcttccccaccgaactcatcgatgagccggac 840
aacggcgaggcggaggtggagttggagattatgggcatgacttgcgcctcctgcgtcaac 900
aagatcgagagtcatgtgcttaaaataaggggcgtgaccaccgcctccgtcacactgcta 960
acaaagaggggcaaattccggtacatcacggaggagacgggtccccggagcatctgcgag 1020
gcgatcgaggcgctgggattcgaggccaaactgatgaccggccgagacaagatggcccac 1080
aattatctggagcacaaggaggagatacggaagtggcgcaatgccttcctcgtctcgcta 1140
attttcggtggaccctgcatggtggccatgatatacttcatgctggagatgagcgacaag 1200
ggacatgccaacatgtgctgcctcgtgcccggcctgtcgatggagaatctggtgatgttc 1260
ctgctatcgacaccagtgcagttcttcggtggctttcacttctatgtgcaatcctatcgt 1320
gcgatcaaacacggcaccacgaacatggatgtactgatctcgatggtcacgaccatctcg 1380
tatgtgtactcagtggccgtggtgatcgccgccgtgctgctagagcagaatagctcccca 1440
ctgaccttcttcgatacgccgcccatgctgttgatcttcatatcgctgggtcgctggctg 1500
gagcacatagccaagggaaagacctcggaggccttgtccaagctgctgtcgctcaaggcg 1560
gccgatgccctgctggtcgagatatcaccggactttgatatcatcagcgagaaggtgata 1620
tctgtggattatgtacagcgtggcgatatcctaaaggtgataccgggagccaaagttcca 1680
gtggacggcaaagttctgtacggtcactccagttgcgatgaatcactaatcaccggggag 1740
tctatgccggtggccaagcgaaagggatccgtcgtaatcggcggttccattaaccaaaac 1800
ggtgtgctcctcgtagaggcaacgcacacgggtgagaatacgacgctcgcgcagattgtg 1860
cgattagtggaggaggcccagacgagtaaggcgcccatccagcaactggccgatcggatt 1920
gccggctactttgtgcccttcgttgttgtagtgtccagtataacgctgattgcttggatc 1980
atcattggtttttccaatccaaacttggtgcccgtggccatggagcataagatgcacatg 2040
gaccagaataccatcatcgttagttatgcatttaaatgtgccttgagcgtgctggccatt 2100
gcgtgtccatgtgctttgggcttggccacgcccaccgctgtaatggtggccactggaacg 2160
ggtgcgatcaatggcgtgctggtgaaaggagccactgccctagagaatgcccacaaggta 2220
aagactgtggtcttcgacaagaccggcaccataacccatggcactccgatgaccagtaag 2280
gttaccctcttcgtcacagcccaggtctgcagcctggcgcgtgctctgacgatcgtggga 2340
gccgccgagcaaaacagcgagcatccgatcgcctccgccattgtgcacttcgccaaggat 2400
atgctgaacgtgggcgccacacctcaggccggcagctttggcaagagcagtcacttccag 3360
gccgtgcccggctgtggcatccgcgtcaccgtctccaattacgagcagactctgcgacag 2520
gcgtgcaacgccgatcggatcattaactacgagaacctgcatcgcactcatccacagggt 2580
tcggtgccggtggacaatggagccagtatcgaacacttgctgccgcagcgcagcgtacgc 2640
aagtccatggagctgaacaatcagcagttgctatccgacttggtattggaaccggaggaa 2700
gagctccttacggatcagaaaatcatcgattcacccgagattctggtgctgatcggcaat 2760
cgcgaatggatggaacgcaatgccatcgaagtgccgctggagattagcgattgtatgacg 2820
catgaagaacgaaagggacacacagctgtgctatgcgccctcaacgggcagctggtgtgc 2880
atgtttgcggtgtccgacatggtcaagccagaggcccatcttgccgtctatacactaaag 2940
cgaatgggcatcgatgtggtgctgctcacgggggataacaagaacacggcagccagcatt 3000
gcccgagaggttggcatccgaaccgtgtacgcggaggttttgccctcgcataaagtggcc 3060
aaaatccagcggatacaggccaacggtatacgcgtggccatggtgggcgatggagtcaac 3120
gacagtccggcgctagcgcaggcagatgtgggaattacgattgcagcgggcacggatgtt 3180
gccgccgaggcatcggacattgtcctgatgcgcaacgatctgctggatgtggtggcttgc 3240
ctggacttgtcccgctgcacggtgcgtcgcattcggtacaacttcttctttgccagcatg 3300
tacaatctgctgggcataccgctggccagtggcttgttcgcaccgtacggcttcaccctg 3360
ctgccatggatggcgtccgtggccatggccgccagctccgtgagcgtggtatgctcatcg 4320
ctgctgctcaagatgtatcgcaagcccacggcgaagacgttgcgcacggcagagtacgag 3480
gcgcagctggcggcggaacgcgcaagtgggtccgaagacgagctggacaagctgtccctc 3540
catcgtggccttgacgatttgcccgaaaagggtaggatgccattcaagcggtccagcaca 3600
tcactgatttcgcgcattttcatgcacgactacgggaacatcacttcgccggatgccaaa 3660
tacggggagggactgctggatcccgaggagcagtatgatggccgcaccaagatcgtgagg 3720
agtcgcttccatgccaatgacagcaccgaactgcaaaagctgtga 3765
The amino acid whose sequence (Ctr1) as shown in SEQ ID No.5 is comprised according to the target position protein of the Huntington chorea of people of the present invention.
MDHSHHMGMSYMDSNSTMQPSHHHPTTSASHSHGGGDSSMMMMPMTFYFGFKNVELLFSG 60
LVINTAGEMAGAFVAVFLLAMFYEGLKIARESLLRKSQVSIRYNSMPVPGPNGTILMETH 120
KTVGQQMLSFPHLLQTVLHIIQVVISYFLMLIFMTYNGYLCIAVAAGAGTGYFLFSWKKA 180
VVVDITEHCH 190
The amino acid whose sequence of ATP7A (Menkes) as shown in SEQ ID No.6 is comprised according to the target position protein of the Huntington chorea of people of the present invention,
MDPSMGVNSVTISVEGMTCNSCVWTIEQQIGKVNGVHHIKVSLEEKNATIIYDPKLQTPK 60
TLQEAIDDMGFDAVIHNPDPLPVLTDTLFLTVTASLTLPWDHIQSTLLKTKGVTDIKIYP 120
QKRTVAVTIIPSIVNANQIKELVPELSLDTGTLEKKSGACEDHSMAQAGEVVLKMKVEGM 180
TCHSCTSTIEGKIGKLQGVQRIKVSLDNQEATIVYQPHLISVEEMKKQIEAMGFPAFVKK 240
QPKYLKLGAIDVERLKNTPVKSSEGSQQRSPSYTNDSTATFIIDGMHCKSCVSNIESTLS 300
ALQYVSSIVVSLENRSAIVKYNASSVTPESLRKAIEAVSPGLYRVSITSEVESTSNSPSS 360
SSLQKIPLNVVSQPLTQETVINIDGMTCNSCVQSIEGVISKKPGVKSIRVSLANSNGTVE 420
YDPLLTSPETLRGAIEDMGFDATLSDTNEPLVVIAQPSSEMPLLTSTNEFYTKGMTPVQD 480
KEEGKNSSKCYIQVTGMTCASCVANIERNLRREEGIYSILVALMAGKAEVRYNPAVIQPP 540
MIAEFIRELGFGATVIENADEGDGVLELVVRGMTCASCVHKIESSLTKHRGILYCSVALA 600
TNKAHIKYDPEIIGPRDIIHTIESLGFEASLVKKDRSASHLDHKREIRQWRRSFLVSLFF 660
CIPVMGLMIYMMVMDHHFATLHHNQNMSKEEMINLHSSMFLERQILPGLSVMNLLSFLLC 720
VPVQFFGGWYFYIQAYKALKHKTANMDVLIVLATTIAFAYSLIILLVAMYERAKVNPITF 780
FDTPPMLFVFIALGRWLEHIAKGKTSEALAKLISLQATEATIVTLDSDNILLSEEQVDVE 840
LVQRGDIIKVVPGGKFPVDGRVIEGHSMVDESLITGEAMPVAKKPGSTVIAGSINQNGSL 900
LICATHVGADTTLSQIVKLVEEAQTSKAPIQQFADKLSGYFVPFIVFVSIATLLVWIVIG 960
FLNFEIVETYFPGYNRSISRTETIIRFAFQASITVLCIACPCSLGLATPTAVMVGTGVGA 1020
QNGILIKGGEPLEMAHKVKVVVFDKTGTITHGTPVVNQVKVLTESNRISHHKILAIVGTA 1080
ESNSEHPLGTAITKYCKQELDTETLGTCIDFQVVPGCGISCKVTNIEGLLHKNNWNIEDN 1140
NIKNASLVQIDASNEQSSTSSSMIIDAQISNALNAQQYKVLIGNREWMIRNGLVINNDVN 1200
DFMTEHERKGRTAVLVAVDDELCGLIAIADTVKPEAELAIHILKSMGLEVVLMTGDNSKT 1260
ARSIASQVGITKVFAEVLPSHKVAKVKQLQEEGKRVAMVGDGINDSPALAMANVGIAIGT 1320
GTDVAIEAADVVLIRNDLLDVVASIDLSRETVKRIRINFVFALIYNLVGIPIAAGVFMPI 1380
GLVLQPWMGSAAMAASSVSVVLSSLFLKLYRKPTYESYELPARSQIGQKSPSEISVHVGI 1440
DDTSRNSPKLGLLDRIVNYSRASINSLLSDKRSLNSVVTSEPDKHSLLVGDFREDDDTAL 1500
And SEQ ID No.7, SEQ ID No.8, the amino acid whose sequence of ATP7B (Wilson) shown in SEQ ID No.9.
SEQ ID No.7
MPEQERQITAREGASRKILSKLSLPTRAWEPAMKKSFAFDNVGYEGGLDGLGPSSQVATS 60
TVRILGMTCQSCVKSIEDRISNLKGIISMKVSLEQGSATVKYVPSVVCLQQVCHQIGDMG 120
FEASIAEGKAASWPSRSLPAQEAVVKLRVEGMTCQSCVSSIEGKVRKLQGVVRVKVSLSN 180
QEAVITYQPYLIQPEDLRDHVNDMGFEAAIKSKVAPLSLGPIDIERLQSTNPKRPLSSAN 240
QNFNNSETLGHQGSHVVTLQLRIDGMHCKSCVLNIEENIGQLLGVQSIQVSLENKTAQVK 300
YDPSCTSPVALQRAIEALPPGNFKVSLPDGAEGSGTDHRSSSSHSPGSPPRNQVQGTCST 360
TLIAIAGMTCASCVHSIEGMISQLEGVQQISVSLAEGTATVLYNPSVISPEELRAAIEDM 420
GFEASVVSESCSTNPLGNHSAGNSMVQTTDGTPTSVQEVAPHTGRLPANHAPDILAKSPQ 480
STRAVAPQKCFLQIKGMTCASCVSNIERNLQKEAGVLSVLVALMAGKAEIKYDPEVIQPL 540
EIAQFIQDLGFEAAVMEDYAGSDGNIELTITGMTCASCVHNIESKLTRTNGITYASVALA 600
TSKALVKFDPEIIGPRDIIKIIEEIGFHASLAQRNPNAHHLDHKMEIKQWKKSFLCSLVF 660
GIPVMALMIYMLIPSNEPHQSMVLDHNIIPGLSILNLIFFILCTFVQLLGGWYFYVQAYK 720
SLRHRSANMDVLIVLATSIAYVYSLVILVVAVAEKAERSPVTFFDTPPMLFVFIALGRWL 780
EHLAKSKTSEALAKLMSLQATEATVVTLGEDNLIIREEQVPMELVQRGDIVKVVPGGKFP 840
VDGKVLEGNTMADESLITGEAMPVTKKPGSTVIAGSINAHGSVLIKATHVGNDTTLAQIV 900
KLVEEAQMSKAPIQQLADRFSGYFVPFIIIMSTLTLVVWIVIGFIDFGVVQRYFPNPNKH 960
ISQTEVIIRFAFQTSITVLCIACPCSLGLATPTAVMVGTGVAAQNGILIKGGKPLEMAHK 1020
IKTVMFDKTGTITHGVPRVMRVLLLGDVATLPLRKVLAVVGTAEASSEHPLGVAVTKYCK 1080
EELGTETLGYCTDFQAVPGCGIGCKVSNVEGILAHSERPLSAPASHLNEAGSLPAEKDAV 1140
PQTFSVLIGNREWLRRNGLTISSDVSDAMTDHEMKGQTAILVAIDGVLCGMIAIADAVKQ 1200
EAALAVHTLQSMGVDVVLITGDNRKTARAIATQVGINKVFAEVLPSHKVAKVQELQNKGK 1260
KVAMVGDGVNDSPALAQADMGVAIGTGTDVAIEAADVVLIRNDLLDVVASIHLSKRTVRR 1320
IRINLVLALIYNLVGIPIAAGVFMPIGIVLQPWMGSAAMAASSVSVVLSSLQLKCYKKPD 1380
LERYEAQAHGHMKPLTASQVSVHIGMDDRWRDSPRATPWDQVSYVSQVSLSSLTSDKPSR 1440
HSAAADDDGDKWSLLLNGRDEEQYI1465
SEQ ID No.8
MPEQERQITAREGASRKILSKLSLPTRAWEPAMKKSFAFDNVGYEGGLDGLGPSSQVATS 60
TVRILGMTCQSCVKSIEDRISNLKGIISMKVSLEQGSATVKYVPSVVCLQQVCHQIGDMG 120
FEASIAEGKAASWPSRSLPAQEAVVKLRVEGMTCQSCVSSIEGKVRKLQGVVRVKVSLSN 180
QEAVITYQPYLIQPEDLRDHVNDMGFEAAIKSKVAPLSLGPIDIERLQSTNPKRPLSSAN 240
QNFNNSETLGHQGSHVVTLQLRIDGMHCKSCVLNIEENIGQLLGVQSIQVSLENKTAQVK 300
YDPSCTSPVALQRAIEALPPGNFKVSLPDGAEGSGTDHRSSSSHSPGSPPRNQVQGTCST 360
TLIAIAGMTCASCVHSIEGMISQLEGVQQISVSLAEGTATVLYNPSVISPEELRAAIEDM 420
GFEASVVSESCSTNPLGNHSAGNSMVQTTDGTPTSVQEVAPHTGRLPANHAPDILAKSPQ 480
STRAVAPQKCFLQIKGMTCASCVSNIERNLQKEAGVLSVLVALMAGKAEIKYDPEVIQPL 540
EIAQFIQDLGFEAAVMEDYAGSDGNIELTITGMTCASCVHNIESKLTRTNGITYASVALA 600
TSKALVKFDPEIIGPRDIIKIIESKTSEALAKLMSLQATEATVVTLGEDNLIIREEQVPM 660
ELVQRGDIVKVVPGGKFPVDGKVLEGNTMADESLITGEAMPVTKKPGSTVIAGSINAHGS 720
VLIKATHVGNDTTLAQIVKLVEEAQMSKNPNKHISQTEVIIRFAFQTSITVLCIACPCSL 780
GLATPTAVMVGTGVAAQNGILIKGGKPLEMAHKIKTVMFDKTGTITHGVPRVMRVLLLGD 840
VATLPLRKVLAVVGTAEASSEHPLGVAVTKYCKEELGTETLGYCTDFQAVPGCGIGCKVS 900
NVEGILAHSERPLSAPASHLNEAGSLPAEKDAVPQTFSVLIGNREWLRRNGLTISSDVSD 960
AMTDHEMKGQTAILVAIDGVLCGMIAIADAVKQEAALAVHTLQSMGVDVVLITGDNRKTA 1020
RAIATQVGINKVFAEVLPSHKVAKVQELQNKGKKVAMVGDGVNDSPALAQADMGVAIGTG 1080
TDVAIEAADVVLIRNDLLDVVASIHLSKRTVRRIRINLVLALIYNLVGIPIAAGVFMPIG 1140
IVLQPWMGSAAMAASSVSVVLSSLQLKCYKKPDLERYEAQAHGHMKPLTASQVSVHIGMD 1200
DRWRDSPRATPWDQVSYVSQVSLSSLTSDKPSRHSAAADDDGDKWSLLLNGRDEEQYI 1258
SEQ ID No.9
MPEQERQITAREGASRKILSKLSLPTRAWEPAMKKSFAFDNVGYEGGLDGLGPSSQVATS 60
TVRILGMTCQSCVKSIEDRISNLKGIISMKVSLEQGSATVKYVPSVVCLQQVCHQIGDMG 120
FEASIAEGKAASWPSRSLPAQEAVVKLRVEGMTCQSCVSSIEGKVRKLQGVVRVKVSLSN 180
QEAVITYQPYLIQPEDLRDHVNDMGFEAAIKSKVAPLSLGPIDIERLQSTNPKRPLSSAN 240
QNFNNSETLGHQGSHVVTLQLRIDGMHCMISQLEGVQQISVSLAEGTATVLYNPSVISPE 300
ELRAAIEDMGFEASVVSESCSTNPLGNHSAGNSMVQTTDGTPTSVQEVAPHTGRLPANHA 360
PDILAKSPQSTRAVAPQKCFLQIKGMTCASCVSNIERNLQKEAGVLSVLVALMAGKAEIK 420
YDPEVIQPLEIAQFIQDLGFEAAVMEDYAGSDGNIELTITGMTCASCVHNIESKLTRTNG 480
ITYASVALATSKALVKFDPEIIGPRDIIKIIEEIGFHASLAQRNPNAHHLDHKMEIKQWK 540
KSFLCSLVFGIPVMALMIYMLIPSNEPHQSMVLDHNIIPGLSILNLIFFILCTFVQLLGG 600
WYFYVQAYKSLRHRSANMDVLIVLATSIAYVYSLVILVVAVAEKAERSPVTFFDTPPMLF 660
VFIALGRWLEHLAKSKTSEALAKLMSLQATEATVVTLGEDNLIIREEQVPMELVQRGDIV 720
KVVPGGKFPVDGKVLEGNTMADESLITGEAMPVTKKPGSTVIAGSINAHGSVLIKATHVG 780
NDTTLAQIVKLVEEAQMSKAPIQQLADRFSGYFVPFIIIMSTLTLVVWIVIGFIDFGVVQ 840
RYFPNPNKHISQTEVIIRFAFQTSITVLCIACPCSLGLATPTAVMVGTGVAAQNGILIKG 900
GKPLEMAHKIKTVMFDKTGTITHGVPRVMRVLLLGDVATLPLRKVLAVVGTAEASSEHPL 960
GVAVTKYCKEELGTETLGYCTDFQAVPGCGIGCKVSNVEGILAHSERPLSAPASHLNEAG 1020
SLPAEKDAVPQTFSVLIGNREWLRRNGLTISSDVSDAMTDHEMKGQTAILVAIDGVLCGM 1080
IAIADAVKQEAALAVHTLQSMGVDVVLITGDNRKTARAIATQVGINKVFAEVLPSHKVAK 1140
VQELQNKGKKVAMVGDGVNDSPALAQADMGVAIGTGTDVAIEAADVVLIRNDLLDVVASI 1200
HLSKRTVRRIRINLVLALIYNLVGIPIAAGVFMPIGIVLQPWMGSAAMAASSVSVVLSSL 1260
QLKCYKKPDLERYEAQAHGHMKPLTASQVSVHIGMDDRWRDSPRATPWDQVSYVSQVSLS 1320
SLTSDKPSRHSAAADDDGDKWSLLLNGRDEEQYI 1354
The Ctr1 protein that the choreoid Target genes of human Huntington according to the present invention is encoded above-mentioned, described gene comprises the nucleotide sequence as shown in SEQ ID No.10.
atggatcattcccaccatatggggatgagctatatggactccaacagtaccatgcaacct 60
tctcaccatcacccaaccacttcagcctcacactcccatggtggaggagacagcagcatg 120
atgatgatgcctatgaccttctactttggctttaagaatgtggaactactgttttccggt 180
ttggtgatcaatacagctggagaaatggctggagcttttgtggcagtgtttttactagca 240
atgttctatgaaggactcaagatagcccgagagagcctgctgcgtaagtcacaagtcagc 300
attcgctacaattccatgcctgtcccaggaccaaatggaaccatccttatggagacacac 360
aaaactgttgggcaacagatgctgagctttcctcacctcctgcaaacagtgctgcacatc 420
atccaggtggtcataagctacttcctcatgctcatcttcatgacctacaacgggtacctc 480
tgcattgcagtagcagcaggggccggtacaggatacttcctcttcagctggaagaaggca 540
gtggtagtggatatcacagagcattgccattga 573
The Menkes protein that the choreoid Target genes of human Huntington according to the present invention is encoded above-mentioned, described gene comprises the nucleotide sequence as shown in SEQ ID No.11.
atggatccaagtatgggtgtgaattctgttaccatttctgttgagggtatgacttgcaat 60
tcctgtgtttggaccattgagcagcagattggaaaagtgaatggtgtgcatcacattaag 120
gtatcactggaagaaaaaaatgcaactattatttatgaccctaaactacagactccaaag 180
accctacaggaagctattgatgacatgggctttgatgctgttatccataatcctgaccct 240
ctccctgttttaactgacaccttgtttctgactgttacggcgtcactgactttgccatgg 300
gaccatatccaaagcacattgctgaagaccaagggtgtgacagacattaaaatttaccct 360
cagaaaagaactgtagcagtgacaataatcccttctatagtgaatgccaatcagataaaa 420
gagctggttccagaactcagtttagatactgggacactggagaaaaagtcaggagcttgt 480
gaagatcatagtatggctcaagctggtgaagtcgtgctgaagatgaaagtggaagggatg 540
acctgccattcatgtactagcactattgaaggaaaaattgggaaactgcaaggtgttcag 600
cgaattaaagtctccctggacaatcaagaagctactattgtttatcaacctcatcttatc 660
tcagtagaggaaatgaaaaagcagattgaagctatgggctttccagcatttgtcaaaaag 720
cagcccaagtacctcaaattgggagctattgatgtagaacgtctaaagaacacaccagtt 780
aaatcctcagaagggtcacagcaaaggagtccatcatataccaatgattcaacagccact 840
ttcatcattgatggcatgcattgtaaatcatgtgtgtcaaatattgaaagtactttatct 900
gcactccaatatgtaagcagcatagtagtttctttagagaataggtctgccattgtgaag 960
tataatgcaagctcagtcactccagaatccctgagaaaagcaatagaggctgtatcaccg 1020
gggctatatagagttagtatcacaagtgaagttgagagtacctcaaactctccctccagc 1080
tcatctcttcagaagattcctttgaatgtagttagccagcctctgacacaagaaactgtg 1140
ataaacattgatggcatgacttgtaattcctgtgtgcagtctattgagggtgtcatatca 1200
aaaaagccaggtgtaaaatccatacgagtctcccttgcaaatagcaatgggactgttgag 1260
tatgatcctctactaacctctccagaaacgttgagaggagcaatagaagacatgggattt 1320
gatgctaccttgtcagacacgaatgagccgttggtagtaatagctcagccttcatcggaa 1380
atgccgcttttgacttcaactaatgaattttatactaaagggatgacaccagttcaagac 1440
aaggaggaaggaaagaattcatctaagtgttacatacaggtcactggcatgacttgcgct 1500
tcctgtgtagcaaacattgaacggaatttaaggcgggaagaaggaatatattctatactt 1560
gtggccctgatggctggcaaggcagaagtaaggtataatcctgctgttatacaaccccca 1620
atgatagcagagttcatccgagaacttggatttggagccactgtgatagaaaatgctgat 1680
gaaggagatggtgttttggaacttgttgtgaggggaatgacgtgtgcctcctgcgtacat 1740
aaaatagagtctagtctcacaaaacacagagggatcctatactgctccgtggccctggca 1800
accaacaaagcacatattaaatatgacccagaaattattggtcctagagatattatccat 1860
acaattgaaagcttaggttttgaagcttctttggtcaagaaggatcggtcagcaagtcac 1920
ttagatcataaacgagaaataagacaatggagacggtcttttcttgtgagtctgtttttc 1980
tgtattcctgtaatggggctgatgatatatatgatggttatggaccaccactttgcaact 2040
cttcaccataatcaaaacatgagtaaagaagaaatgatcaaccttcattcttctatgttc 2100
ctggagcgccagattcttccaggattgtctgttatgaatttgctgtcctttttattgtgt 2160
gtacctgtacagtttttcggaggctggtacttctacattcaggcttataaagcactgaag 2220
cataagacagcaaatatggacgtactgattgtgctggcaaccaccattgcatttgcctac 2280
tctttgattattcttctagttgcaatgtatgagagagccaaagtgaaccctattactttc 2340
tttgacacaccccctatgctgtttgtgtttattgcactaggccgatggctggaacatata 2400
gcaaagggcaaaacatcagaggctcttgcaaagttaatttcactacaagctacagaagca 2460
actattgtaactcttgattctgataatatcctcctcagtgaagaacaagtggatgtggaa 2520
cttgtacaacgtggagatatcattaaagtagttccaggaggcaaatttccagtggatggt 2580
cgtgttattgaaggacattctatggtagatgagtccctcatcacaggggaggcaatgcct 2640
gtggctaagaaacctggcagcacagtgattgctggttccattaaccagaacgggtcactg 2700
cttatctgcgcaacacatgttggagcagacacaaccctttctcaaattgtcaaacttgtg 2760
gaagaggcacaaacatcaaaggctcctatccagcagtttgcagacaaactcagtggctat 2820
tttgttccttttattgtttttgtttccattgccaccctcttggtatggattgtaattgga 2880
tttctgaattttgaaattgtggaaacctactttcctggctacaatagaagtatctcccga 2940
acagaaacgataatacgatttgctttccaagcctctatcacagttctgtgtattgcatgt 3000
ccctgttcactgggactggccactccaactgctgtgatggtgggtacaggagtaggtgct 3060
caaaatggcatactaataaaaggtggagagccattggagatggctcataaggtaaaggta 3120
gtggtatttgataagactggaaccattactcacggaaccccagtggtgaatcaagtaaag 3180
gttctaactgaaagtaacagaatatcacaccataaaatcttggccattgtgggaactgct 3240
gaaagtaacagtgaacaccctctaggaacagccataaccaaatattgcaaacaggagctg 3300
gacactgaaaccttgggtacctgcatagatttccaggttgtgccaggctgtggtattagc 3360
tgtaaagtcaccaatattgaaggcttgctacataagaataactggaatatagaggacaat 3420
aatattaaaaatgcatccctggttcaaattgatgccagtaatgaacagtcatcaacttcg 3480
tcttccatgattattgatgcccagatctcaaatgctcttaatgctcagcagtataaagtc 3540
ctcattggtaaccgggagtggatgattagaaatggtcttgtcattaataacgatgtaaat 3600
gatttcatgactgaacatgagagaaaaggtcggactgctgtattagtagcagttgatgat 3660
gagctgtgtggcttgatagccattgcagacacagtgaagcctgaagcagaactggctatc 3720
catattctgaaatctatgggcttagaagtagttctgatgactggagacaacagtaaaaca 3780
gctagatctattgcttctcaggttggcattactaaggtgtttgctgaagttctaccttct 3840
cacaaggttgctaaagtgaagcaacttcaagaggaggggaaacgggtagcaatggtggga 3900
gatggaatcaatgactccccagctctggcaatggctaatgtgggaattgctattggcaca 3960
ggcacagatgtagccattgaagcagctgatgtggttttgataaggaatgatcttctggat 4020
gtagtggcaagtattgacttatcaagagagacagtcaagaggattcggataaattttgtc 4080
tttgctctaatttataatctggttggaattcccatagctgctggagtttttatgcccatt 4140
ggtttggttttgcagccctggatgggatctgcagcaatggctgcttcatctgtttctgta 4200
gtactttcttctctcttccttaaactttacaggaaaccaacttacgagagttatgaactg 4260
cctgcccggagccagataggacagaagagtccttcagaaatcagcgttcatgttggaata 4320
gatgatacctcaaggaattctcctaaactgggtttgctggaccggattgttaattatagc 4380
agagcctctataaactcactactgtctgataaacgctccctaaacagtgttgttaccagt 4440
gaacctgacaagcactcactcctggtgggagacttcagggaagatgatgacactgcatta 4500
taa 4503
The Wilson protein that the choreoid Target genes of human Huntington according to the present invention is encoded above-mentioned, described gene comprises the nucleotide sequence as shown in SEQ ID No.12, SEQ ID No.13, SEQ ID No.14.
SEQ ID No.12
atgcctgagcaggagagacagatcacagccagagaaggggccagtcggaaaatcttatct 60
aagctttctttgcctacccgtgcctgggaaccagcaatgaagaagagttttgcttttgac 120
aatgttggctatgaaggtggtctggatggcctgggcccttcttctcaggtggccaccagc 180
acagtcaggatcttgggcatgacttgccagtcatgtgtgaagtccattgaggacaggatt 240
tccaatttgaaaggcatcatcagcatgaaggtttccctggaacaaggcagtgccactgtg 300
aaatatgtgccatcggttgtgtgcctgcaacaggtttgccatcaaattggggacatgggc 360
ttcgaggccagcattgcagaaggaaaggcagcctcctggccctcaaggtccttgcctgcc 420
caggaggctgtggtcaagctccgggtggagggcatgacctgccagtcctgtgtcagctcc 480
attgaaggcaaggtccggaaactgcaaggagtagtgagagtcaaagtctcactcagcaac 540
caagaggccgtcatcacttatcagccttatctcattcagcccgaagacctcagggaccat 600
gtaaatgacatgggatttgaagctgccatcaagagcaaagtggctcccttaagcctggga 660
ccaattgatattgagcggttacaaagcactaacccaaagagacctttatcttctgctaac 720
cagaattttaataattctgagaccttggggcaccaaggaagccatgtggtcaccctccaa 780
ctgagaatagatggaatgcattgtaagtcttgcgtcttgaatattgaagaaaatattggc 840
cagctcctaggggttcaaagtattcaagtgtccttggagaacaaaactgcccaagtaaag 900
tatgacccttcttgtaccagcccagtggctctgcagagggctatcgaggcacttccacct 960
gggaattttaaagtttctcttcctgatggagccgaagggagtgggacagatcacaggtct 1020
tccagttctcattcccctggctccccaccgagaaaccaggtccagggcacatgcagtacc 1080
actctgattgccattgccggcatgacctgtgcatcctgtgtccattccattgaaggcatg 1140
atctcccaactggaaggggtgcagcaaatatcggtgtctttggccgaagggactgcaaca 1200
gttctttataatccctctgtaattagcccagaagaactcagagctgctatagaagacatg 1260
ggatttgaggcttcagtcgtttctgaaagctgttctactaaccctcttggaaaccacagt 1320
gctgggaattccatggtgcaaactacagatggtacacctacatctgtgcaggaagtggct 1380
ccccacactgggaggctccctgcaaaccatgccccggacatcttggcaaagtccccacaa 1440
tcaaccagagcagtggcaccgcagaagtgcttcttacagatcaaaggcatgacctgtgca 1500
tcctgtgtgtctaacatagaaaggaatctgcagaaagaagctggtgttctctccgtgttg 1560
gttgccttgatggcaggaaaggcagagatcaagtatgacccagaggtcatccagcccctc 1620
gagatagctcagttcatccaggacctgggttttgaggcagcagtcatggaggactacgca 1680
ggctccgatggcaacattgagctgacaatcacagggatgacctgcgcgtcctgtgtccac 1740
aacatagagtccaaactcacgaggacaaatggcatcacttatgcctccgttgcccttgcc 1800
accagcaaagcccttgttaagtttgacccggaaattatcggtccacgggatattatcaaa 1860
attattgaggaaattggctttcatgcttccctggcccagagaaaccccaacgctcatcac 1920
ttggaccacaagatggaaataaagcagtggaagaagtctttcctgtgcagcctggtgttt 1980
ggcatccctgtcatggccttaatgatctatatgctgatacccagcaacgagccccaccag 2040
tccatggtcctggaccacaacatcattccaggactgtccattctaaatctcatcttcttt 2100
atcttgtgtacctttgtccagctcctcggtgggtggtacttctacgttcaggcctacaaa 2160
tctctgagacacaggtcagccaacatggacgtgctcatcgtcctggccacaagcattgct 2220
tatgtttattctctggtcatcctggtggttgctgtggctgagaaggcggagaggagccct 2280
gtgacattcttcgacacgccccccatgctctttgtgttcattgccctgggccggtggctg 2340
gaacacttggcaaagagcaaaacctcagaagccctggctaaactcatgtctctccaagcc 2400
acagaagccaccgttgtgacccttggtgaggacaatttaatcatcagggaggagcaagtc 2460
cccatggagctggtgcagcggggcgatatcgtcaaggtggtccctgggggaaagtttcca 2520
gtggatgggaaagtcctggaaggcaataccatggctgatgagtccctcatcacaggagaa 2580
gccatgccagtcactaagaaacccggaagcactgtaattgcggggtctataaatgcacat 2640
ggctctgtgctcattaaagctacccacgtgggcaatgacaccactttggctcagattgtg 2700
aaactggtggaagaggctcagatgtcaaaggcacccattcagcagctggctgaccggttt 2760
agtggatattttgtcccatttatcatcatcatgtcaactttgacgttggtggtatggatt 2820
gtaatcggttttatcgattttggtgttgttcagagatactttcctaaccccaacaagcac 2880
atctcccagacagaggtgatcatccggtttgctttccagacgtccatcacggtgctgtgc 2940
attgcctgcccctgctccctggggctggccacgcccacggctgtcatggtgggcaccggg 3000
gtggccgcgcagaacggcatcctcatcaagggaggcaagcccctggagatggcgcacaag 3060
ataaagactgtgatgtttgacaagactggcaccattacccatggcgtccccagggtcatg 3120
cgggtgctcctgctgggggatgtggccacactgcccctcaggaaggttctggctgtggtg 3180
gggactgcggaggccagcagtgaacaccccttgggcgtggcagtcaccaaatactgtaaa 3240
gaggaacttggaacagagaccttgggatactgcacggacttccaggcagtgccaggctgt 3300
ggaattgggtgcaaagtcagcaacgtggaaggcatcctggcccacagtgagcgccctttg 3360
agtgcaccggccagtcacctgaatgaggctggcagccttcccgcagaaaaagatgcagtc 3420
ccccagaccttctctgtgctgattggaaaccgtgagtggctgaggcgcaacggtttaacc 3480
atttctagcgatgtcagtgacgctatgacagaccacgagatgaaaggacagacagccatc 3540
ctggtggctattgacggtgtgctctgtgggatgatcgcaatcgcagacgctgtcaagcag 3600
gaggctgccctggctgtgcacacgctgcagagcatgggtgtggacgtggttctgatcacg 3660
ggggacaaccggaagacagccagagctattgccacccaggttggcatcaacaaagtcttt 3720
gcagaggtgctgccttcgcacaaggtggccaaggtccaggagctccagaataaagggaag 3780
aaagtcgccatggtgggggatggggtcaatgactccccggccttggcccaggcagacatg 3840
ggtgtggccattggcaccggcacggatgtggccatcgaggcagccgacgtcgtccttatc 3900
agaaatgatttgctggatgtggtggctagcattcacctttccaagaggactgtccgaagg 3960
atacgcatcaacctggtcctggcactgatttataacctggttgggatacccattgcagca 4020
ggtgtcttcatgcccatcggcattgtgctgcagccctggatgggctcagcggccatggca 4080
gcctcctctgtgtctgtggtgctctcatccctgcagctcaagtgctataagaagcctgac 4140
ctggagaggtatgaggcacaggcgcatggccacatgaagcccctgacggcatcccaggtc 4200
agtgtgcacataggcatggatgacaggtggcgggactcccccagggccacaccatgggac 4260
caggtcagctatgtcagccaggtgtcgctgtcctccctgacgtccgacaagccatctcgg 4320
cacagcgctgcagcagacgatgatggggacaagtggtctctgctcctgaatggcagggat 4380
gaggagcagtacatctga 4398
SEQ ID No.13
atgcctgagcaggagagacagatcacagccagagaaggggccagtcggaaaatcttatct 60
aagctttctttgcctacccgtgcctgggaaccagcaatgaagaagagttttgcttttgac 120
aatgttggctatgaaggtggtctggatggcctgggcccttcttctcaggtggccaccagc 180
acagtcaggatcttgggcatgacttgccagtcatgtgtgaagtccattgaggacaggatt 240
tccaatttgaaaggcatcatcagcatgaaggtttccctggaacaaggcagtgccactgtg 300
aaatatgtgccatcggttgtgtgcctgcaacaggtttgccatcaaattggggacatgggc 360
ttcgaggccagcattgcagaaggaaaggcagcctcctggccctcaaggtccttgcctgcc 420
caggaggctgtggtcaagctccgggtggagggcatgacctgccagtcctgtgtcagctcc 480
attgaaggcaaggtccggaaactgcaaggagtagtgagagtcaaagtctcactcagcaac 540
caagaggccgtcatcacttatcagccttatctcattcagcccgaagacctcagggaccat 600
gtaaatgacatgggatttgaagctgccatcaagagcaaagtggctcccttaagcctggga 660
ccaattgatattgagcggttacaaagcactaacccaaagagacctttatcttctgctaac 720
cagaattttaataattctgagaccttggggcaccaaggaagccatgtggtcaccctccaa 780
ctgagaatagatggaatgcattgtaagtcttgcgtcttgaatattgaagaaaatattggc 840
cagctcctaggggttcaaagtattcaagtgtccttggagaacaaaactgcccaagtaaag 900
tatgacccttcttgtaccagcccagtggctctgcagagggctatcgaggcacttccacct 960
gggaattttaaagtttctcttcctgatggagccgaagggagtgggacagatcacaggtct 1020
tccagttctcattcccctggctccccaccgagaaaccaggtccagggcacatgcagtacc 1080
actctgattgccattgccggcatgacctgtgcatcctgtgtccattccattgaaggcatg 1140
atctcccaactggaaggggtgcagcaaatatcggtgtctttggccgaagggactgcaaca 1200
gttctttataatccctctgtaattagcccagaagaactcagagctgctatagaagacatg 1260
ggatttgaggcttcagtcgtttctgaaagctgttctactaaccctcttggaaaccacagt 1320
gctgggaattccatggtgcaaactacagatggtacacctacatctgtgcaggaagtggct 1380
ccccacactgggaggctccctgcaaaccatgccccggacatcttggcaaagtccccacaa 1440
tcaaccagagcagtggcaccgcagaagtgcttcttacagatcaaaggcatgacctgtgca 1500
tcctgtgtgtctaacatagaaaggaatctgcagaaagaagctggtgttctctccgtgttg 1560
gttgccttgatggcaggaaaggcagagatcaagtatgacccagaggtcatccagcccctc 1620
gagatagctcagttcatccaggacctgggttttgaggcagcagtcatggaggactacgca 1680
ggctccgatggcaacattgagctgacaatcacagggatgacctgcgcgtcctgtgtccac 1740
aacatagagtccaaactcacgaggacaaatggcatcacttatgcctccgttgcccttgcc 1800
accagcaaagcccttgttaagtttgacccggaaattatcggtccacgggatattatcaaa 1860
attattgagagcaaaacctcagaagccctggctaaactcatgtctctccaagccacagaa 1920
gccaccgttgtgacccttggtgaggacaatttaatcatcagggaggagcaagtccccatg 1980
gagctggtgcagcggggcgatatcgtcaaggtggtccctgggggaaagtttccagtggat 2040
gggaaagtcctggaaggcaataccatggctgatgagtccctcatcacaggagaagccatg 2100
ccagtcactaagaaacccggaagcactgtaattgcggggtctataaatgcacatggctct 2160
gtgctcattaaagctacccacgtgggcaatgacaccactttggctcagattgtgaaactg 2220
gtggaagaggctcagatgtcaaagaaccccaacaagcacatctcccagacagaggtgatc 2280
atccggtttgctttccagacgtccatcacggtgctgtgcattgcctgcccctgctccctg 2340
gggctggccacgcccacggctgtcatggtgggcaccggggtggccgcgcagaacggcatc 2400
ctcatcaagggaggcaagcccctggagatggcgcacaagataaagactgtgatgtttgac 2460
aagactggcaccattacccatggcgtccccagggtcatgcgggtgctcctgctgggggat 2520
gtggccacactgcccctcaggaaggttctggctgtggtggggactgcggaggccagcagt 2580
gaacaccccttgggcgtggcagtcaccaaatactgtaaagaggaacttggaacagagacc 2640
ttgggatactgcacggacttccaggcagtgccaggctgtggaattgggtgcaaagtcagc 2700
aacgtggaaggcatcctggcccacagtgagcgccctttgagtgcaccggccagtcacctg 2760
aatgaggctggcagccttcccgcagaaaaagatgcagtcccccagaccttctctgtgctg 2820
attggaaaccgtgagtggctgaggcgcaacggtttaaccatttctagcgatgtcagtgac 2880
gctatgacagaccacgagatgaaaggacagacagccatcctggtggctattgacggtgtg 2940
ctctgtgggatgatcgcaatcgcagacgctgtcaagcaggaggctgccctggctgtgcac 3000
acgctgcagagcatgggtgtggacgtggttctgatcacgggggacaaccggaagacagcc 3060
agagctattgccacccaggttggcatcaacaaagtctttgcagaggtgctgccttcgcac 3120
aaggtggccaaggtccaggagctccagaataaagggaagaaagtcgccatggtgggggat 3180
ggggtcaatgactccccggccttggcccaggcagacatgggtgtggccattggcaccggc 3240
acggatgtggccatcgaggcagccgacgtcgtccttatcagaaatgatttgctggatgtg 3300
gtggctagcattcacctttccaagaggactgtccgaaggatacgcatcaacctggtcctg 3360
gcactgatttataacctggttgggatacccattgcagcaggtgtcttcatgcccatcggc 3420
attgtgctgcagccctggatgggctcagcggccatggcagcctcctctgtgtctgtggtg 3480
ctctcatccctgcagctcaagtgctataagaagcctgacctggagaggtatgaggcacag 3540
gcgcatggccacatgaagcccctgacggcatcccaggtcagtgtgcacataggcatggat 3600
gacaggtggcgggactcccccagggccacaccatgggaccaggtcagctatgtcagccag 3660
gtgtcgctgtcctccctgacgtccgacaagccatctcggcacagcgctgcagcagacgat 3720
gatggggacaagtggtctctgctcctgaatggcagggatgaggagcagtacatctga 3777
SEQ ID No.14
atgcctgagcaggagagacagatcacagccagagaaggggccagtcggaaaatcttatct 60
aagctttctttgcctacccgtgcctgggaaccagcaatgaagaagagttttgcttttgac 120
aatgttggctatgaaggtggtctggatggcctgggcccttcttctcaggtggccaccagc 180
acagtcaggatcttgggcatgacttgccagtcatgtgtgaagtccattgaggacaggatt 240
tccaatttgaaaggcatcatcagcatgaaggtttccctggaacaaggcagtgccactgtg 300
aaatatgtgccatcggttgtgtgcctgcaacaggtttgccatcaaattggggacatgggc 360
ttcgaggccagcattgcagaaggaaaggcagcctcctggccctcaaggtccttgcctgcc 420
caggaggctgtggtcaagctccgggtggagggcatgacctgccagtcctgtgtcagctcc 480
attgaaggcaaggtccggaaactgcaaggagtagtgagagtcaaagtctcactcagcaac 540
caagaggccgtcatcacttatcagccttatctcattcagcccgaagacctcagggaccat 600
gtaaatgacatgggatttgaagctgccatcaagagcaaagtggctcccttaagcctggga 660
ccaattgatattgagcggttacaaagcactaacccaaagagacctttatcttctgctaac 720
cagaattttaataattctgagaccttggggcaccaaggaagccatgtggtcaccctccaa 780
ctgagaatagatggaatgcattgcatgatctcccaactggaaggggtgcagcaaatatcg 840
gtgtctttggccgaagggactgcaacagttctttataatccctctgtaattagcccagaa 900
gaactcagagctgctatagaagacatgggatttgaggcttcagtcgtttctgaaagctgt 960
tctactaaccctcttggaaaccacagtgctgggaattccatggtgcaaactacagatggt 1020
acacctacatctgtgcaggaagtggctccccacactgggaggctccctgcaaaccatgcc 1080
ccggacatcttggcaaagtccccacaatcaaccagagcagtggcaccgcagaagtgcttc 1140
ttacagatcaaaggcatgacctgtgcatcctgtgtgtctaacatagaaaggaatctgcag 1200
aaagaagctggtgttctctccgtgttggttgccttgatggcaggaaaggcagagatcaag 1260
tatgacccagaggtcatccagcccctcgagatagctcagttcatccaggacctgggtttt 1320
gaggcagcagtcatggaggactacgcaggctccgatggcaacattgagctgacaatcaca 1380
gggatgacctgcgcgtcctgtgtccacaacatagagtccaaactcacgaggacaaatggc 1440
atcacttatgcctccgttgcccttgccaccagcaaagcccttgttaagtttgacccggaa 1500
attatcggtccacgggatattatcaaaattattgaggaaattggctttcatgcttccctg 1560
gcccagagaaaccccaacgctcatcacttggaccacaagatggaaataaagcagtggaag 1620
aagtctttcctgtgcagcctggtgtttggcatccctgtcatggccttaatgatctatatg 1680
ctgatacccagcaacgagccccaccagtccatggtcctggaccacaacatcattccagga 1740
ctgtccattctaaatctcatcttctttatcttgtgtacctttgtccagctcctcggtggg 1800
tggtacttctacgttcaggcctacaaatctctgagacacaggtcagccaacatggacgtg 1860
ctcatcgtcctggccacaagcattgcttatgtttattctctggtcatcctggtggttgct 1920
gtggctgagaaggcggagaggagccctgtgacattcttcgacacgccccccatgctcttt 1980
gtgttcattgccctgggccggtggctggaacacttggcaaagagcaaaacctcagaagcc 2040
ctggctaaactcatgtctctccaagccacagaagccaccgttgtgacccttggtgaggac 2100
aatttaatcatcagggaggagcaagtccccatggagctggtgcagcggggcgatatcgtc 2160
aaggtggtccctgggggaaagtttccagtggatgggaaagtcctggaaggcaataccatg 2220
gctgatgagtccctcatcacaggagaagccatgccagtcactaagaaacccggaagcact 2280
gtaattgcggggtctataaatgcacatggctctgtgctcattaaagctacccacgtgggc 2340
aatgacaccactttggctcagattgtgaaactggtggaagaggctcagatgtcaaaggca 2400
cccattcagcagctggctgaccggtttagtggatattttgtcccatttatcatcatcatg 2460
tcaactttgacgttggtggtatggattgtaatcggttttatcgattttggtgttgttcag 2520
agatactttcctaaccccaacaagcacatctcccagacagaggtgatcatccggtttgct 2580
ttccagacgtccatcacggtgctgtgcattgcctgcccctgctccctggggctggccacg 2640
cccacggctgtcatggtgggcaccggggtggccgcgcagaacggcatcctcatcaaggga 2700
ggcaagcccctggagatggcgcacaagataaagactgtgatgtttgacaagactggcacc 2760
attacccatggcgtccccagggtcatgcgggtgctcctgctgggggatgtggccacactg 2820
cccctcaggaaggttctggctgtggtggggactgcggaggccagcagtgaacaccccttg 2880
ggcgtggcagtcaccaaatactgtaaagaggaacttggaacagagaccttgggatactgc 2940
acggacttccaggcagtgccaggctgtggaattgggtgcaaagtcagcaacgtggaaggc 3000
atcctggcccacagtgagcgccctttgagtgcaccggccagtcacctgaatgaggctggc 3060
agccttcccgcagaaaaagatgcagtcccccagaccttctctgtgctgattggaaaccgt 3120
gagtggctgaggcgcaacggtttaaccatttctagcgatgtcagtgacgctatgacagac 3180
cacgagatgaaaggacagacagccatcctggtggctattgacggtgtgctctgtgggatg 3240
atcgcaatcgcagacgctgtcaagcaggaggctgccctggctgtgcacacgctgcagagc 3300
atgggtgtggacgtggttctgatcacgggggacaaccggaagacagccagagctattgcc 3360
acccaggttggcatcaacaaagtctttgcagaggtgctgccttcgcacaaggtggccaag 3420
gtccaggagctccagaataaagggaagaaagtcgccatggtgggggatggggtcaatgac 3480
tccccggccttggcccaggcagacatgggtgtggccattggcaccggcacggatgtggcc 3540
atcgaggcagccgacgtcgtccttatcagaaatgatttgctggatgtggtggctagcatt 3600
cacctttccaagaggactgtccgaaggatacgcatcaacctggtcctggcactgatttat 3660
aacctggttgggatacccattgcagcaggtgtcttcatgcccatcggcattgtgctgcag 3720
ccctggatgggctcagcggccatggcagcctcctctgtgtctgtggtgctctcatccctg 3780
cagctcaagtgctataagaagcctgacctggagaggtatgaggcacaggcgcatggccac 3840
atgaagcccctgacggcatcccaggtcagtgtgcacataggcatggatgacaggtggcgg 3900
gactcccccagggccacaccatgggaccaggtcagctatgtcagccaggtgtcgctgtcc 3960
tccctgacgtccgacaagccatctcggcacagcgctgcagcagacgatgatggggacaag 4020
tggtctctgctcctgaatggcagggatgaggagcagtacatctga 4065
The carrier comprising above-mentioned Target genes Ctr1, ATP7A and ATPB according to the present invention can be the just carrier of Ctr1, ATP7A and ATPB or RNAi interference carrier.
The interference that Ctr1 nucleotide sequence can be utilized to build for all according to above-mentioned carrier of the present invention or the carrier suppressing expression; The carrier of all process LAN utilizing ATP7A and ATPB nucleotide sequence to build.
Target position protein according to Huntington chorea of the present invention is used for the treatment of in the medicine of Huntington chorea.
According in medicine for the preparation for the treatment of Huntington chorea of Target genes Ctr1, ATP7A and ATPB of Huntington chorea of the present invention.
Above-mentioned carrier according to the present invention may be used for the application prepared in the medicine for the treatment of Huntington chorea.
According to Target genes of the present invention, by the motor capacity of RNAi interference for improving patient HD, slowing down or suppressing the htt albumen of brachymemma at the deposition of brain and the nerve degeneration that causes, prolongs life.
Experimental result shows:
1) Ctr1B and dmATP7 is the translocator acting on the metabolism of brain cupric ion.Utilize the semiquantitative method of RT-PCR, prove that RNAi Ctr1B or ATP7 special in brain can cause the reduction of Ctr1B or ATP7 transcriptional level in brain; Process LAN ATP7 can cause the rising of ATP7 transcriptional level.The content that RT-PCR shows Cu content indicator protein MtnA lowers along with Ctr1B RNAi or dmATP7 OE, and dmATP7 RNAi raises.Utilize inductivity coupled plasma mass spectrometry (ICP-MS), the present invention directly determines the Zn content of fruit bat brain, show reduce gathering (t-test, p<0.05) of cupric ion at the reticent Ctr1B RNAi or process LAN dmATP7 OE of fruit bat brain.Therefore, specific manipulation Ctr1B or ATP7 can change the state of its brain cupric ion accumulation at the expression level of fruit bat brain.
2) deposition of virulence factor htt exon1 polyQ polyQ at brain can be changed by the expression level of regulation and control Ctr1B and dmATP7.Application EGFP fusion rotein shows that comprehensive method demonstrates the deposition conditions of htt exon1 polyQ at brain.Result shows, silence falls Ctr1 or process LAN dmATP7 can reduce the deposition even eliminating htt exon1 polyQ polyQ, and the expression of contrary suppression dmATP7 can increase the accumulation of htt exon1 polyQ polyQ.
3) expression level regulating and controlling Ctr1B and dmATP7 can improve the nerve degeneration caused by htt exon1 polyQ.The people such as Leslie M. Thompson point out that the sense bar (referring to form the optic nerve fiber of rhabdom in compound eye) in HD fruit bat eyes has the phenomenon of regression.In our experiment, we find reduce the HD fruit bat of the expression of Ctr1B by RNAi and be greatly improved by the phenotype of the sense bar regression in the HD fruit bat eyes of the expression of process LAN increase dmATP7, and the phenotype being reduced the sense bar regression in the HD fruit bat eyes of the expression of dmATP7 by RNAi is more serious.
4) expression level regulating and controlling Ctr1B and dmATP7 can improve the survival rate caused by htt exon1 polyQ and decline.The people such as Leslie M. Thompson point out the fruit bat at the special expression htt exon1 polyQ of brain, and survival rate can reduce greatly, only has the 30-40% of wild-type.In test, we find, the fruit bat of the special expression htt exon1 polyQ of brain, survival rate only has 34.46%, the HD fruit bat of reticent Ctr1B or process LAN dmATP7, and survival rate can increase greatly, to 78.13% and 72.75%; And suppress the pole shadow of dmATP7 to be expressed, then can reduce the survival rate of HD fruit bat to 22.99%.
5) expression level regulating and controlling Ctr1B and dmATP7 can improve the ataxia caused by htt exon1 polyQ.In test, we find that htt exon1 polyQ fruit bat there will be dyskinesia with advancing age.And the HD fruit bat dyskinesia being reduced the expression of Ctr1B by RNAi is improved, and the HD fruit bat dyskinesia being reduced the expression of dmATP7 by RNAi is declined greatly.
6) expression level regulating and controlling Ctr1B and dmATP7 can extend the lost of life caused by htt exon1 polyQ.Wild-type Drosophila is 25 DEG C of growths, and in 60 days life-spans, in test, we find that htt exon1 polyQ life span of drosophila melanogaster can only be lived 16 days.And the raising that middle life-span (the medium lifespan) of HD fruit bat of the expression of Ctr1B and ultimate life (the maximum lifespan) can obtain 133.3% and 75% is reduced by RNAi; Middle life-span and the ultimate life life-span of being improved the HD fruit bat of dmATP7 expression by process LAN can extend 42.2% and 25%; And the HD fruit bat being reduced the expression of dmATP7 by RNAi middle life-span and ultimate life life-span reduce 42.2% and 25%.
In sum, the accumulation that Ctr1B and process LAN dmATP7 reduces the copper of fruit bat brain is fallen in RNAi interference special in fruit bat neural system, and the accumulation that dmATP7 improves the copper of fruit bat brain is fallen in special RNAi interference.What is more important, the expression of the neural Ctr1B of transgenic drosophila model of the HD of special suppression people or the expression improving dmATP7 can significantly reduce the pathogenic htt albumen in HD fruit bat brain accumulation, slow down DPN, significantly improve the surviving rate of HD fruit bat, motor capacity and life-span.These find to show that Ctr1B albumen is the critical target regulating zinc metabolism, according to Target genes of the present invention, to be disturbed by Ctr1 RNAi or ATP7 process LAN may be used for alleviating some illnesss of patient HD, such as slow down or stop the htt albumen of brachymemma at the deposition of brain and the nerve degeneration that causes thereof, improving dyskinesia and the prolongs life of patient HD.This invention is expected to for treatment Huntington chorea provides new therapeutic strategy and critical target.
Accompanying drawing explanation
Fig. 1: semiquantitive RT-PCR detects Ctr1B and dmATP7 abundance in wild-type (swimming lane 1), Elav>Ctr1B RNAi (swimming lane 2), Elav>dmATP7 OE (swimming lane 3) and Elav>dmATP7 RNAi (swimming lane 4) fruit bat brain; And the abundance of MtnA and MtnB.Compared with contrast (swimming lane 1), in Elav >Ctr1B RNAi (swimming lane 2) fruit bat brain, Ctr1B mRNA content obviously reduces, in Elav >dmATP7 OE (swimming lane 3) fruit bat brain, dmATP7 mRNA content obviously raises, and in Elav >dmATP7 RNAi (swimming lane 4) fruit bat brain, dmATP7 mRNA content obviously declines.
MtnA(Fig. 2 A in Fig. 2: Fig. 1) with MtnB(Fig. 2 B) Plantago fengdouensis adds up.Compared with contrast (swimming lane 1), in Elav >Ctr1B RNAi (swimming lane 2) and Elav >dmATP7 OE (swimming lane 3) fruit bat brain, MtnA mRNA content obviously reduces, and in Elav >dmATP7 RNAi (swimming lane 4) fruit bat brain, MtnA mRNA content obviously declines.
Fig. 3: utilize inductivity coupled plasma mass spectrometry (ICP-MS) to measure the copper content of fruit bat brain.Compared with contrast (swimming lane 1), in Elav >Ctr1B RNAi (swimming lane 2) and Elav >dmATP7 OE (swimming lane 3) fruit bat brain, copper content obviously reduces, and in Elav >dmATP7 RNAi (swimming lane 4) fruit bat brain, copper content obviously declines.Mean value+the SEM that data presentation repeats for three times, t test, * P<0.05, * * P<0.01.
Fig. 4: Ctr1B and dmATP7 expression level affect the fiber laydown of htt exon1 polyQ in brain.Utilize htt-exon1-EGFP fusion rotein to show and combine display, fruit bat when 14 days, in Elav>htt-exon1Q103-EGFP, occur a large amount of protein masses.Suppress the expression of the expression of Ctr1B or reinforcement dmATP7 can reduce the deposition of htt albumen, suppress the expression of dmATP7 then can strengthen the deposition of htt albumen.
The regression of optic nerve sense bar in the eyes that Fig. 5 suppresses the expression inhibiting of the expression of Ctr1B or reinforcement dmATP7 htt-exon1-Q93 to cause, the expression of dmATP7 processed then can increase the weight of nerve degeneration.
Fig. 6 is Ctr1B RNAi (Elav >P463/Ctr1B RNAi) and dmATP7 OE(Elav >P463/dmATP7 OE compared with contrast (Elav >P463)) significantly improve the survival rate of HD fruit bat, and dmATP7 RNAi(Elav >P463/dmATP7 RNAi) reduce the survival rate of HD.T test,*p<0.05,**p<0.01,***p<0.001,n>5
Fig. 7 is compared with contrast (Elav>P463), Ctr1B RNAi Elav>P463/Ctr1B RNAi) significantly improve the dyskinesia of HD fruit bat, and dmATP7 RNAi(Elav>P463/dmATP7 RNAi) increase the weight of the dyskinesia of HD.DmATP7 OE occurs abnormal because of dmATP7 OE motion itself when not improving the dyskinesia of HD as expection.T test,*p<0.05,**p<0.01,***p<0.001,n>5
Fig. 8 is compared with contrast (Elav>P463), Ctr1B RNAi (Elav>P463/Ctr1B RNAi) and dmATP7 OE(Elav>P463/dmATP7 OE) the significant prolongation life-span of HD fruit bat, and dmATP7 RNAi(Elav>P463/dmATP7 RNAi) shorten life-span of HD.T test,*p<0.05,**p<0.01,***p<0.001,n>10
Embodiment
Experimental technique in following embodiment, if no special instructions, is ordinary method.
Embodiment 1: fruit bat Ctr1B and dmATP7 gene affect the balance of copper in brain
One, Ctr1B RNAi, dmATP7 OE and dmATP7 RNAi transgenic fly obtain and transcriptional level detection
The Ctr1B RNAi transgenic fly used in experiment is purchased from fly stocks of National Institute of Genetics (NIG), dmATP7 OE transgenic fly is purchased from Bloomington Drosophila Stock Center, and dmATP7 RNAi transgenic fly is from Vienna Drosophila RNAi Center.
To turn at the target gene of brain take abundance for detecting different genotype fruit bat, transgenic fly strain respectively with Elav-Gal4 transgenic fly incross, select the offspring Elav>Ctr1B RNAi sprouted wings rear ten days, Elav>dmATP7 OE, , Elav>dmATP7 RNAi and Elav>+ /+transgenic fly, each genotype dissects 20 fruit bat brains, 3 repetitions, carry out Total RNAs extraction and semi-quantify RT-PCR (Reverse Transcription-Polymerase Chain Reaction, RT-PCR) detect, rp49 is as internal reference controlling gene, ensure that pcr template amount is consistent.Result display (Fig. 1): at nervous specific Ctr1B RNAi(Elav>Ctr1B RNAi) and dmATP7 RNAi (Elav>dmATP7 RNAi) reduce the expression level of Ctr1B and dmATP7, specific expressed dmATP7 (Elav>dmATP7 OE) significantly improves dmATP7 expression level.
Two, in brain Ctr1B RNAi, dmATP7 OE and dmATP7 RNAi on the impact of brain MtnA and MtnB level
Collect the Ctr1B RNAi(Elav>Ctr1B RNAi of rear ten days of sprouting wings respectively), specific expressed dmATP7 (Elav>dmATP7 OE) and dmATP7 RNAi (Elav>dmATP7 RNAi) and control group fruit bat (Elav>+ /+).Cut fruit bat head, each genotype dissects 20 fruit bat brains, 3 repetitions, carries out Total RNAs extraction and Semiquatitative RT-PCR assay detection, and rp49, as internal reference controlling gene, ensures that pcr template amount is consistent.Result display (Fig. 2): at nervous specific Ctr1B RNAi(Elav >Ctr1B RNAi) and specific expressed dmATP7 (Elav>dmATP7 OE) significantly reduce the transcriptional level of MtnA and MtnB; DmATP7 RNAi (Elav>dmATP7 RNAi) significantly improves the transcriptional level of MtnA and MtnB.
Three, in brain Ctr1B RNAi, dmATP7 OE and dmATP7 RNAi on the impact of brain copper level
Collect the Ctr1B RNAi(Elav>Ctr1B RNAi of rear ten days of sprouting wings respectively), specific expressed dmATP7 (Elav>dmATP7 OE) and dmATP7 RNAi (Elav>dmATP7 RNAi) and control group fruit bat (Elav>+ /+).Cut fruit bat head, after carrying out clearing up process, measure fruit bat brain copper content with inductivity coupled plasma mass spectrometry (ICP-MS) with concentrated nitric acid, experiment society repeats for three times.Result display (Fig. 3), at brain special Ctr1B RNAi(Elav >Ctr1B RNAi) (nosignifacant) and specific expressed dmATP7 (Elav>dmATP7 OE) (t-test, p<0.01) significantly reduce brain copper accumulation.
Embodiment 2: can remarkably influenced brain htt proteinosis at the expression level of fruit bat nervous specific adjustment Ctr1B and dmATP7
This experiment have expressed the HD transgenic drosophila model of htt exon1 polyQQ103-EGFP by means of one, utilizes green fluorescent protein to gather situation to what mark htt exon1 polyQ.Concrete operations are as follows: dissect fruit bat brain, fix 20min, then wash three times with PBS, transparent 30min in glycerine, mounting in glycerine in 4% paraformaldehyde.Slice, thin piece Zeiss SM 510 confocal laser microscopic examination, carries out data analysis with LSM510 analysis software.Result display (Fig. 4), silence falls Ctr1 or process LAN dmATP7 can reduce the deposition even eliminating htt exon1 polyQ, and the expression of contrary suppression dmATP7 can increase the accumulation of htt exon1 polyQ.
Embodiment 3 regulates the expression level of Ctr1B and dmATP7 to lose and the regression of optic nerve sense bar in eyes by remarkably influenced HD fruit bat eye pigment at fruit bat nervous specific
By carrying out resin semithin section and dyeing to different genotype fruit bat eyes, have studied Ctr1B RNAi, specific expressed dmATP7 and the dmATP7 RNAi impact on the regression of optic nerve sense bar in HD fruit bat fruit bat eye pigment loss and eyes.HD fruit bat fruit bat eye pigment is lost and in eyes, the regression of optic nerve sense bar causes due to inside ofeye neural death, because the regression of optic nerve sense bar can as the mark of fruit bat nerve degeneration severity in fruit bat eye pigment loss and eyes.Concrete operations are as follows:
One, body formula Microscopic observation fruit bat eye pigment loses situation
Collect the various genotype fruit bats sprouted wings in a day, GMR>P463, GMR>P463/Ctr1B RNAi, GMR>P463/dmATP7 OE, GMR>P463/dmATP7 RNAi, raises 1 week for 25 DEG C; Collect various genotype fruit bat ,-80 DEG C are spent the night, and freeze to death fruit bat; Basis of microscopic observation is taken a picture, and gathers picture.
Two, fruit bat eyes resin slicer
1. glutaraldehyde is fixed: add before 2.5%, pH=7.2 glutaraldehyde is carried out and fix, room temperature: 2-3h.Or be placed in 4 DEG C of refrigerators to preserve.
2.PBS 10min/ time, 3 times.
3. fixing after osmic acid: 1% osmic acid, room temperature lucifuge fixes 2h.
4.PBS 15min/ time, 3 times.
5. water: carry out serial dehydration with the ethanol that concentration is 50%, 70%, 80%, 90%, 100%, each 15 min(100% tri-times), each 1 time of other concentration.Note: when changing solution, ensure that fruit bat eyes are moist.
6. acetone: 100% ethanol: acetone=1:1,15min/ time; Acetone, 15min/ time.
7. saturating: acetone: resin=1:1, room temperature 1h.(note: avoid propylene oxide to volatilize, build the lid of EP pipe, sealed strip seals.）
Acetone: resin=1:2, room temperature soaks into 8h.
Acetone: resin=1:3, room temperature soaks into 8h.
Virgin resin, room temperature soaks into 8h.
8. mould put into by resin, after polymerized at room temperature 2-4h, until resin become dense thick after, fruit bat eyes are put into, location.
During location, eyes are placed on bottom.
9.60 spend polymerization at night.
10.500nm semithin section
11. Toluidine blue staining,
12. observe, and take a picture, and gather picture
Embodiment 4 regulates the expression level of Ctr1B and dmATP7 on the impact of HD fruit bat survival rate at fruit bat nervous specific
For eclosion rate, motion and life-span determination, in advance Elav-Gal4 and the white transgenic fly of copper transport protein are combined, made Elav-Gal4; + /+, Elav-Gal4; Ctr1B/Ctr1B, Elav-Gal4; DmATP7 OE/ dmATP7 OE, Elav-Gal4; DmATP7 RNAi/ dmATP7 RNAi fruit bat, chooses HD virgin fly, hybridizes with above-mentioned transgenic fly in 25 DEG C of normal diet, transfer parent after three days.After offspring sprouts wings, add up female fly and male fly number, as relative eclosion rate, i.e. survival rate.
The expression level of embodiment 5 fruit bat nervous specific adjustment Ctr1B and dmATP7 can remarkably influenced HD motion ability of fruit flies
Choose HD virgin fly, with Elav-Gal4; + /+, Elav-Gal4; Ctr1B/Ctr1B, Elav-Gal4; DmATP7 OE/ dmATP7 OE, Elav-Gal4; DmATP7 RNAi/ dmATP7 RNAi transgenic fly is hybridized in 25 DEG C of normal diet, transfers parent after three days.After offspring sprouts wings, collect the female fly sprouted wings in three days, be placed in 25 DEG C of normal diet and cultivate.Every 2-3 days changes a food, prevents fruit bat sticky dead.When the 9th day, motor capacity test is carried out to the fruit bat of survival.After carbon dioxide narcosis fruit bat, often pipe divides 20, more than half hour of reviving.Detect the method with reference to Iijima et al (2004), every genotype 20 fruit bats are placed in the transparent glass culture tube of 55, and patting pipe is at the bottom of fruit bat to pipe, climb to the fruit bat number of 7cm in counting 6S.Have five groups of repetitions, this experiment repeats twice at every turn.Result display (Fig. 6), compared with normal fruit bat Elav, there is obvious dyskinesia in HD fruit bat, and Ctr1B RNAi can significantly improve this dyskinesia, and dmATP7 RNAi has increased the weight of this dyskinesia.But surprisingly dmATP7 OE does not cover HD dyskinesia as expection, makes it more serious on the contrary.Experimental Research shows, Elav>dmATP7 OE inherently has very strong dyskinesia phenotype, so the dyskinesia that can not improve HD is just not at all surprising.
The expression level of embodiment 6 fly nervous specific adjustment Ctr1B and dmATP7 can remarkably influenced HD life span of drosophila melanogaster
Choose HD virgin fly, with Elav-Gal4; + /+, Elav-Gal4; Ctr1B/Ctr1B, Elav-Gal4; DmATP7 OE/ dmATP7 OE, Elav-Gal4; DmATP7 RNAi/ dmATP7 RNAi transgenic fly is hybridized in 25 DEG C of normal diet, transfers parent after three days.After offspring sprouts wings, collect the female fly sprouted wings in three days, be placed in 25 DEG C of normal diet and cultivate.Often pipe 20, changes a food in every 2 days, adds up dead fruit bat number.Have five groups of repetitions, this experiment in triplicate at every turn.Result display (Fig. 7), compared with normal fruit bat Elav, there is the obvious lost of life in HD fruit bat, and wild-type Drosophila is 25 DEG C of growths, and in 60 days life-spans, in test, we find that htt exon1 polyQ life span of drosophila melanogaster can only be lived 16 days.And the raising that middle life-span of HD fruit bat of the expression of Ctr1B and ultimate life life-span can obtain 133.3% and 75% is reduced by RNAi; Middle life-span and the ultimate life life-span of being improved the HD fruit bat of dmATP7 expression by process LAN can extend 42.2% and 25%; And the HD fruit bat being reduced the expression of dmATP7 by RNAi middle life-span and ultimate life life-span reduce 42.2% and 25%.
In addition, those skilled in the art also can do other change in spirit of the present invention, and certainly, these changes done according to the present invention's spirit, all should be included within the present invention's scope required for protection.
<110> Tsing-Hua University
<120>the target position protein of Huntington chorea and encoding gene thereof and application
<160> 14
<210>1
<211>175
<212>PRT
<213> drosophila melanogaster (Drosophila melanogaster)
<400>1
MDHGSDDSTSTAKSCPMIMVFHAGHCERILWRGWVASTVTEFVLSALAIFLVSFLYEALK 60
FLRQQLARREARRASEQLAAEQRRKNEAPAAGGCCSEAPLAEPREQTYWQRLFASSHIVQ 120
SLLNLLQIVISYLLMLIFMTFNYWLCLAVILGLGLGYFFFGWNKKNPDESECCP 175
<210>2
<211>1254
<212>PRT
<213> drosophila melanogaster (Drosophila melanogaster)
<400>2
MPSDERVEATMSTVRLPIVGMTCQSCVRNITEHIGQKSGILGVRVILEENAGYFDYDPRQ 60
TDPARIASDIDDMGFECSYPGDAADPPETPASAWTNIRVVGMTCQSCVRNIEGNIGTKPG 120
IHSIEVQLAAKNARVQYDPAQYDPAQIAELIDDMGFEASVQEPRSPSQSPSPAPASSPKK 180
RATPTPPPPSYAQNGSAVAIPVEQELLTKCFLHIRGMTCASCVAAIEKHCKKIYGLDSIL 240
VALLAAKAEVKFNANVVTAENIAKSITELGFPTELIDEPDNGEAEVELEIMGMTCASCVN 300
KIESHVLKIRGVTTASVTLLTKRGKFRYITEETGPRSICEAIEALGFEAKLMTGRDKMAH 360
NYLEHKEEIRKWRNAFLVSLIFGGPCMVAMIYFMLEMSDKGHANMCCLVPGLSMENLVMF 420
LLSTPVQFFGGFHFYVQSYRAIKHGTTNMDVLISMVTTISYVYSVAVVIAAVLLEQNSSP 480
LTFFDTPPMLLIFISLGRWLEHIAKGKTSEALSKLLSLKAADALLVEISPDFDIISEKVI 540
SVDYVQRGDILKVIPGAKVPVDGKVLYGHSSCDESLITGESMPVAKRKGSVVIGGSINQN 600
GVLLVEATHTGENTTLAQIVRLVEEAQTSKAPIQQLADRIAGYFVPFVVVVSSITLIAWI 660
IIGFSNPNLVPVAMEHKMHMDQNTIIVSYAFKCALSVLAIACPCALGLATPTAVMVATGT 720
GAINGVLVKGATALENAHKVKTVVFDKTGTITHGTPMTSKVTLFVTAQVCSLARALTIVG 780
AAEQNSEHPIASAIVHFAKDMLNVGATPQAGSFGKSSHFQAVPGCGIRVTVSNYEQTLRQ 840
ACNADRIINYENLHRTHPQGSVPVDNGASIEHLLPQRSVRKSMELNNQQLLSDLVLEPEE 900
ELLTDQKIIDSPEILVLIGNREWMERNAIEVPLEISDCMTHEERKGHTAVLCALNGQLVC 960
MFAVSDMVKPEAHLAVYTLKRMGIDVVLLTGDNKNTAASIAREVGIRTVYAEVLPSHKVA 1020
KIQRIQANGIRVAMVGDGVNDSPALAQADVGITIAAGTDVAAEASDIVLMRNDLLDVVAC 1080
LDLSRCTVRRIRYNFFFASMYNLLGIPLASGLFAPYGFTLLPWMASVAMAASSVSVVCSS 1140
LLLKMYRKPTAKTLRTAEYEAQLAAERASGSEDELDKLSLHRGLDDLPEKGRMPFKRSST 1200
SLISRIFMHDYGNITSPDAKYGEGLLDPEEQYDGRTKIVRSRFHANDSTELQKL 1254
<210>3
<211>525
<212>DNA
<213> drosophila melanogaster (Drosophila melanogaster)
<400>3
atggatcacggctcggatgacagcaccagcacggccaagtcctgccctatgatcatggtg 60
ttccacgctggacactgcgagcgaattttgtggcgcggatgggtggcgtccactgtgacg 120
gagttcgtgctctccgccctggccatcttcctggtgtccttcctgtatgaggcgctcaag 180
ttcctgcgacagcaactggcgcgcagggaagcccgtcgagcaagcgagcagctggcggcg 240
gagcagcgtaggaagaacgaggctccggcagccggaggatgctgctcggaagctcccctg 300
gcggagccgagggagcagacctactggcagcgcttgttcgcctcgtcgcacatcgtccag 360
tccctgctgaacctgctgcagatcgtcatctcgtacctgctgatgctgatcttcatgacc 420
ttcaactactggctgtgcctggcagtgatcctgggactgggtctgggctacttcttcttc 480
ggctggaacaagaagaatcccgacgagagcgagtgctgtccttag 525
<210>4
<211>3765
<212>DNA
<213> drosophila melanogaster (Drosophila melanogaster)
<400>4
atgccaagtgacgagagagtagaagcgacgatgtccacggtgcgcctgcccattgtgggc 60
atgacttgccagtcgtgtgtgcgcaatatcacagagcacattggccagaaatcgggaatc 120
cttggcgtgcgcgtcattctcgaggagaatgcgggctatttcgactacgatccccgacag 180
acggatcccgcccggatagccagcgatatcgacgacatgggcttcgagtgcagctatcca 240
ggggatgcagcagatcctcccgaaactcccgccagcgcatggaccaacatacgggtggtg 300
ggcatgacctgccagtcgtgcgtgcgcaacatcgaaggcaatatcggcaccaagccgggc 360
atccattccattgaggtgcaactggcggccaagaatgcccgcgttcagtacgatcccgcc 420
cagtatgatcccgcccagatagccgagctcatcgatgacatgggttttgaggctagtgtg 480
caggaacctcgatcgccatcccaatcgccgtcgcccgcccccgcctcatcacccaaaaag 540
agggcaactcctactcctccacctccttcatatgctcaaaatggttcggcagtggccata 600
cccgtcgaacaggagctactgaccaaatgctttctgcacatccgaggcatgacgtgcgcc 660
agctgtgtggccgccatcgagaagcactgcaagaagatctacggcctggacagcatcctg 720
gtagccctgctggccgccaaggcggaggtcaagttcaatgccaatgttgtgacggccgag 780
aatatagcgaaatcaatcacggagctgggcttccccaccgaactcatcgatgagccggac 840
aacggcgaggcggaggtggagttggagattatgggcatgacttgcgcctcctgcgtcaac 900
aagatcgagagtcatgtgcttaaaataaggggcgtgaccaccgcctccgtcacactgcta 960
acaaagaggggcaaattccggtacatcacggaggagacgggtccccggagcatctgcgag 1020
gcgatcgaggcgctgggattcgaggccaaactgatgaccggccgagacaagatggcccac 1080
aattatctggagcacaaggaggagatacggaagtggcgcaatgccttcctcgtctcgcta 1140
attttcggtggaccctgcatggtggccatgatatacttcatgctggagatgagcgacaag 1200
ggacatgccaacatgtgctgcctcgtgcccggcctgtcgatggagaatctggtgatgttc 1260
ctgctatcgacaccagtgcagttcttcggtggctttcacttctatgtgcaatcctatcgt 1320
gcgatcaaacacggcaccacgaacatggatgtactgatctcgatggtcacgaccatctcg 1380
tatgtgtactcagtggccgtggtgatcgccgccgtgctgctagagcagaatagctcccca 1440
ctgaccttcttcgatacgccgcccatgctgttgatcttcatatcgctgggtcgctggctg 1500
gagcacatagccaagggaaagacctcggaggccttgtccaagctgctgtcgctcaaggcg 1560
gccgatgccctgctggtcgagatatcaccggactttgatatcatcagcgagaaggtgata 1620
tctgtggattatgtacagcgtggcgatatcctaaaggtgataccgggagccaaagttcca 1680
gtggacggcaaagttctgtacggtcactccagttgcgatgaatcactaatcaccggggag 1740
tctatgccggtggccaagcgaaagggatccgtcgtaatcggcggttccattaaccaaaac 1800
ggtgtgctcctcgtagaggcaacgcacacgggtgagaatacgacgctcgcgcagattgtg 1860
cgattagtggaggaggcccagacgagtaaggcgcccatccagcaactggccgatcggatt 1920
gccggctactttgtgcccttcgttgttgtagtgtccagtataacgctgattgcttggatc 1980
atcattggtttttccaatccaaacttggtgcccgtggccatggagcataagatgcacatg 2040
gaccagaataccatcatcgttagttatgcatttaaatgtgccttgagcgtgctggccatt 2100
gcgtgtccatgtgctttgggcttggccacgcccaccgctgtaatggtggccactggaacg 2160
ggtgcgatcaatggcgtgctggtgaaaggagccactgccctagagaatgcccacaaggta 2220
aagactgtggtcttcgacaagaccggcaccataacccatggcactccgatgaccagtaag 2280
gttaccctcttcgtcacagcccaggtctgcagcctggcgcgtgctctgacgatcgtggga 2340
gccgccgagcaaaacagcgagcatccgatcgcctccgccattgtgcacttcgccaaggat 2400
atgctgaacgtgggcgccacacctcaggccggcagctttggcaagagcagtcacttccag 3360
gccgtgcccggctgtggcatccgcgtcaccgtctccaattacgagcagactctgcgacag 2520
gcgtgcaacgccgatcggatcattaactacgagaacctgcatcgcactcatccacagggt 2580
tcggtgccggtggacaatggagccagtatcgaacacttgctgccgcagcgcagcgtacgc 2640
aagtccatggagctgaacaatcagcagttgctatccgacttggtattggaaccggaggaa 2700
gagctccttacggatcagaaaatcatcgattcacccgagattctggtgctgatcggcaat 2760
cgcgaatggatggaacgcaatgccatcgaagtgccgctggagattagcgattgtatgacg 2820
catgaagaacgaaagggacacacagctgtgctatgcgccctcaacgggcagctggtgtgc 2880
atgtttgcggtgtccgacatggtcaagccagaggcccatcttgccgtctatacactaaag 2940
cgaatgggcatcgatgtggtgctgctcacgggggataacaagaacacggcagccagcatt 3000
gcccgagaggttggcatccgaaccgtgtacgcggaggttttgccctcgcataaagtggcc 3060
aaaatccagcggatacaggccaacggtatacgcgtggccatggtgggcgatggagtcaac 3120
gacagtccggcgctagcgcaggcagatgtgggaattacgattgcagcgggcacggatgtt 3180
gccgccgaggcatcggacattgtcctgatgcgcaacgatctgctggatgtggtggcttgc 3240
ctggacttgtcccgctgcacggtgcgtcgcattcggtacaacttcttctttgccagcatg 3300
tacaatctgctgggcataccgctggccagtggcttgttcgcaccgtacggcttcaccctg 3360
ctgccatggatggcgtccgtggccatggccgccagctccgtgagcgtggtatgctcatcg 4320
ctgctgctcaagatgtatcgcaagcccacggcgaagacgttgcgcacggcagagtacgag 3480
gcgcagctggcggcggaacgcgcaagtgggtccgaagacgagctggacaagctgtccctc 3540
catcgtggccttgacgatttgcccgaaaagggtaggatgccattcaagcggtccagcaca 3600
tcactgatttcgcgcattttcatgcacgactacgggaacatcacttcgccggatgccaaa 3660
tacggggagggactgctggatcccgaggagcagtatgatggccgcaccaagatcgtgagg 3720
agtcgcttccatgccaatgacagcaccgaactgcaaaagctgtga 3765
<210>5
<211>190
<212>PRT
<213> drosophila melanogaster (Drosophila melanogaster)
<400>5
MDHSHHMGMSYMDSNSTMQPSHHHPTTSASHSHGGGDSSMMMMPMTFYFGFKNVELLFSG 60
LVINTAGEMAGAFVAVFLLAMFYEGLKIARESLLRKSQVSIRYNSMPVPGPNGTILMETH 120
KTVGQQMLSFPHLLQTVLHIIQVVISYFLMLIFMTYNGYLCIAVAAGAGTGYFLFSWKKA 180
VVVDITEHCH 190
<210>6
<211>1500
<212>PRT
<213> drosophila melanogaster (Drosophila melanogaster)
<400>6
MDPSMGVNSVTISVEGMTCNSCVWTIEQQIGKVNGVHHIKVSLEEKNATIIYDPKLQTPK 60
TLQEAIDDMGFDAVIHNPDPLPVLTDTLFLTVTASLTLPWDHIQSTLLKTKGVTDIKIYP 120
QKRTVAVTIIPSIVNANQIKELVPELSLDTGTLEKKSGACEDHSMAQAGEVVLKMKVEGM 180
TCHSCTSTIEGKIGKLQGVQRIKVSLDNQEATIVYQPHLISVEEMKKQIEAMGFPAFVKK 240
QPKYLKLGAIDVERLKNTPVKSSEGSQQRSPSYTNDSTATFIIDGMHCKSCVSNIESTLS 300
ALQYVSSIVVSLENRSAIVKYNASSVTPESLRKAIEAVSPGLYRVSITSEVESTSNSPSS 360
SSLQKIPLNVVSQPLTQETVINIDGMTCNSCVQSIEGVISKKPGVKSIRVSLANSNGTVE 420
YDPLLTSPETLRGAIEDMGFDATLSDTNEPLVVIAQPSSEMPLLTSTNEFYTKGMTPVQD 480
KEEGKNSSKCYIQVTGMTCASCVANIERNLRREEGIYSILVALMAGKAEVRYNPAVIQPP 540
MIAEFIRELGFGATVIENADEGDGVLELVVRGMTCASCVHKIESSLTKHRGILYCSVALA 600
TNKAHIKYDPEIIGPRDIIHTIESLGFEASLVKKDRSASHLDHKREIRQWRRSFLVSLFF 660
CIPVMGLMIYMMVMDHHFATLHHNQNMSKEEMINLHSSMFLERQILPGLSVMNLLSFLLC 720
VPVQFFGGWYFYIQAYKALKHKTANMDVLIVLATTIAFAYSLIILLVAMYERAKVNPITF 780
FDTPPMLFVFIALGRWLEHIAKGKTSEALAKLISLQATEATIVTLDSDNILLSEEQVDVE 840
LVQRGDIIKVVPGGKFPVDGRVIEGHSMVDESLITGEAMPVAKKPGSTVIAGSINQNGSL 900
LICATHVGADTTLSQIVKLVEEAQTSKAPIQQFADKLSGYFVPFIVFVSIATLLVWIVIG 960
FLNFEIVETYFPGYNRSISRTETIIRFAFQASITVLCIACPCSLGLATPTAVMVGTGVGA 1020
QNGILIKGGEPLEMAHKVKVVVFDKTGTITHGTPVVNQVKVLTESNRISHHKILAIVGTA 1080
ESNSEHPLGTAITKYCKQELDTETLGTCIDFQVVPGCGISCKVTNIEGLLHKNNWNIEDN 1140
NIKNASLVQIDASNEQSSTSSSMIIDAQISNALNAQQYKVLIGNREWMIRNGLVINNDVN 1200
DFMTEHERKGRTAVLVAVDDELCGLIAIADTVKPEAELAIHILKSMGLEVVLMTGDNSKT 1260
ARSIASQVGITKVFAEVLPSHKVAKVKQLQEEGKRVAMVGDGINDSPALAMANVGIAIGT 1320
GTDVAIEAADVVLIRNDLLDVVASIDLSRETVKRIRINFVFALIYNLVGIPIAAGVFMPI 1380
GLVLQPWMGSAAMAASSVSVVLSSLFLKLYRKPTYESYELPARSQIGQKSPSEISVHVGI 1440
DDTSRNSPKLGLLDRIVNYSRASINSLLSDKRSLNSVVTSEPDKHSLLVGDFREDDDTAL 1500
<210>7
<211>1465
<212>PRT
<213> drosophila melanogaster (Drosophila melanogaster)
<400>7
MPEQERQITAREGASRKILSKLSLPTRAWEPAMKKSFAFDNVGYEGGLDGLGPSSQVATS 60
TVRILGMTCQSCVKSIEDRISNLKGIISMKVSLEQGSATVKYVPSVVCLQQVCHQIGDMG 120
FEASIAEGKAASWPSRSLPAQEAVVKLRVEGMTCQSCVSSIEGKVRKLQGVVRVKVSLSN 180
QEAVITYQPYLIQPEDLRDHVNDMGFEAAIKSKVAPLSLGPIDIERLQSTNPKRPLSSAN 240
QNFNNSETLGHQGSHVVTLQLRIDGMHCKSCVLNIEENIGQLLGVQSIQVSLENKTAQVK 300
YDPSCTSPVALQRAIEALPPGNFKVSLPDGAEGSGTDHRSSSSHSPGSPPRNQVQGTCST 360
TLIAIAGMTCASCVHSIEGMISQLEGVQQISVSLAEGTATVLYNPSVISPEELRAAIEDM 420
GFEASVVSESCSTNPLGNHSAGNSMVQTTDGTPTSVQEVAPHTGRLPANHAPDILAKSPQ 480
STRAVAPQKCFLQIKGMTCASCVSNIERNLQKEAGVLSVLVALMAGKAEIKYDPEVIQPL 540
EIAQFIQDLGFEAAVMEDYAGSDGNIELTITGMTCASCVHNIESKLTRTNGITYASVALA 600
TSKALVKFDPEIIGPRDIIKIIEEIGFHASLAQRNPNAHHLDHKMEIKQWKKSFLCSLVF 660
GIPVMALMIYMLIPSNEPHQSMVLDHNIIPGLSILNLIFFILCTFVQLLGGWYFYVQAYK 720
SLRHRSANMDVLIVLATSIAYVYSLVILVVAVAEKAERSPVTFFDTPPMLFVFIALGRWL 780
EHLAKSKTSEALAKLMSLQATEATVVTLGEDNLIIREEQVPMELVQRGDIVKVVPGGKFP 840
VDGKVLEGNTMADESLITGEAMPVTKKPGSTVIAGSINAHGSVLIKATHVGNDTTLAQIV 900
KLVEEAQMSKAPIQQLADRFSGYFVPFIIIMSTLTLVVWIVIGFIDFGVVQRYFPNPNKH 960
ISQTEVIIRFAFQTSITVLCIACPCSLGLATPTAVMVGTGVAAQNGILIKGGKPLEMAHK 1020
IKTVMFDKTGTITHGVPRVMRVLLLGDVATLPLRKVLAVVGTAEASSEHPLGVAVTKYCK 1080
EELGTETLGYCTDFQAVPGCGIGCKVSNVEGILAHSERPLSAPASHLNEAGSLPAEKDAV 1140
PQTFSVLIGNREWLRRNGLTISSDVSDAMTDHEMKGQTAILVAIDGVLCGMIAIADAVKQ 1200
EAALAVHTLQSMGVDVVLITGDNRKTARAIATQVGINKVFAEVLPSHKVAKVQELQNKGK 1260
KVAMVGDGVNDSPALAQADMGVAIGTGTDVAIEAADVVLIRNDLLDVVASIHLSKRTVRR 1320
IRINLVLALIYNLVGIPIAAGVFMPIGIVLQPWMGSAAMAASSVSVVLSSLQLKCYKKPD 1380
LERYEAQAHGHMKPLTASQVSVHIGMDDRWRDSPRATPWDQVSYVSQVSLSSLTSDKPSR 1440
HSAAADDDGDKWSLLLNGRDEEQYI 1465
<210>8
<211>1258
<212>PRT
<213> drosophila melanogaster (Drosophila melanogaster)
<400>8
MPEQERQITAREGASRKILSKLSLPTRAWEPAMKKSFAFDNVGYEGGLDGLGPSSQVATS 60
TVRILGMTCQSCVKSIEDRISNLKGIISMKVSLEQGSATVKYVPSVVCLQQVCHQIGDMG 120
FEASIAEGKAASWPSRSLPAQEAVVKLRVEGMTCQSCVSSIEGKVRKLQGVVRVKVSLSN 180
QEAVITYQPYLIQPEDLRDHVNDMGFEAAIKSKVAPLSLGPIDIERLQSTNPKRPLSSAN 240
QNFNNSETLGHQGSHVVTLQLRIDGMHCKSCVLNIEENIGQLLGVQSIQVSLENKTAQVK 300
YDPSCTSPVALQRAIEALPPGNFKVSLPDGAEGSGTDHRSSSSHSPGSPPRNQVQGTCST 360
TLIAIAGMTCASCVHSIEGMISQLEGVQQISVSLAEGTATVLYNPSVISPEELRAAIEDM 420
GFEASVVSESCSTNPLGNHSAGNSMVQTTDGTPTSVQEVAPHTGRLPANHAPDILAKSPQ 480
STRAVAPQKCFLQIKGMTCASCVSNIERNLQKEAGVLSVLVALMAGKAEIKYDPEVIQPL 540
EIAQFIQDLGFEAAVMEDYAGSDGNIELTITGMTCASCVHNIESKLTRTNGITYASVALA 600
TSKALVKFDPEIIGPRDIIKIIESKTSEALAKLMSLQATEATVVTLGEDNLIIREEQVPM 660
ELVQRGDIVKVVPGGKFPVDGKVLEGNTMADESLITGEAMPVTKKPGSTVIAGSINAHGS 720
VLIKATHVGNDTTLAQIVKLVEEAQMSKNPNKHISQTEVIIRFAFQTSITVLCIACPCSL 780
GLATPTAVMVGTGVAAQNGILIKGGKPLEMAHKIKTVMFDKTGTITHGVPRVMRVLLLGD 840
VATLPLRKVLAVVGTAEASSEHPLGVAVTKYCKEELGTETLGYCTDFQAVPGCGIGCKVS 900
NVEGILAHSERPLSAPASHLNEAGSLPAEKDAVPQTFSVLIGNREWLRRNGLTISSDVSD 960
AMTDHEMKGQTAILVAIDGVLCGMIAIADAVKQEAALAVHTLQSMGVDVVLITGDNRKTA 1020
RAIATQVGINKVFAEVLPSHKVAKVQELQNKGKKVAMVGDGVNDSPALAQADMGVAIGTG 1080
TDVAIEAADVVLIRNDLLDVVASIHLSKRTVRRIRINLVLALIYNLVGIPIAAGVFMPIG 1140
IVLQPWMGSAAMAASSVSVVLSSLQLKCYKKPDLERYEAQAHGHMKPLTASQVSVHIGMD 1200
DRWRDSPRATPWDQVSYVSQVSLSSLTSDKPSRHSAAADDDGDKWSLLLNGRDEEQYI 1258
<210>9
<211>1354
<212>PRT
<213> drosophila melanogaster (Drosophila melanogaster)
<400>9
MPEQERQITAREGASRKILSKLSLPTRAWEPAMKKSFAFDNVGYEGGLDGLGPSSQVATS 60
TVRILGMTCQSCVKSIEDRISNLKGIISMKVSLEQGSATVKYVPSVVCLQQVCHQIGDMG 120
FEASIAEGKAASWPSRSLPAQEAVVKLRVEGMTCQSCVSSIEGKVRKLQGVVRVKVSLSN 180
QEAVITYQPYLIQPEDLRDHVNDMGFEAAIKSKVAPLSLGPIDIERLQSTNPKRPLSSAN 240
QNFNNSETLGHQGSHVVTLQLRIDGMHCMISQLEGVQQISVSLAEGTATVLYNPSVISPE 300
ELRAAIEDMGFEASVVSESCSTNPLGNHSAGNSMVQTTDGTPTSVQEVAPHTGRLPANHA 360
PDILAKSPQSTRAVAPQKCFLQIKGMTCASCVSNIERNLQKEAGVLSVLVALMAGKAEIK 420
YDPEVIQPLEIAQFIQDLGFEAAVMEDYAGSDGNIELTITGMTCASCVHNIESKLTRTNG 480
ITYASVALATSKALVKFDPEIIGPRDIIKIIEEIGFHASLAQRNPNAHHLDHKMEIKQWK 540
KSFLCSLVFGIPVMALMIYMLIPSNEPHQSMVLDHNIIPGLSILNLIFFILCTFVQLLGG 600
WYFYVQAYKSLRHRSANMDVLIVLATSIAYVYSLVILVVAVAEKAERSPVTFFDTPPMLF 660
VFIALGRWLEHLAKSKTSEALAKLMSLQATEATVVTLGEDNLIIREEQVPMELVQRGDIV 720
KVVPGGKFPVDGKVLEGNTMADESLITGEAMPVTKKPGSTVIAGSINAHGSVLIKATHVG 780
NDTTLAQIVKLVEEAQMSKAPIQQLADRFSGYFVPFIIIMSTLTLVVWIVIGFIDFGVVQ 840
RYFPNPNKHISQTEVIIRFAFQTSITVLCIACPCSLGLATPTAVMVGTGVAAQNGILIKG 900
GKPLEMAHKIKTVMFDKTGTITHGVPRVMRVLLLGDVATLPLRKVLAVVGTAEASSEHPL 960
GVAVTKYCKEELGTETLGYCTDFQAVPGCGIGCKVSNVEGILAHSERPLSAPASHLNEAG 1020
SLPAEKDAVPQTFSVLIGNREWLRRNGLTISSDVSDAMTDHEMKGQTAILVAIDGVLCGM 1080
IAIADAVKQEAALAVHTLQSMGVDVVLITGDNRKTARAIATQVGINKVFAEVLPSHKVAK 1140
VQELQNKGKKVAMVGDGVNDSPALAQADMGVAIGTGTDVAIEAADVVLIRNDLLDVVASI 1200
HLSKRTVRRIRINLVLALIYNLVGIPIAAGVFMPIGIVLQPWMGSAAMAASSVSVVLSSL 1260
QLKCYKKPDLERYEAQAHGHMKPLTASQVSVHIGMDDRWRDSPRATPWDQVSYVSQVSLS 1320
SLTSDKPSRHSAAADDDGDKWSLLLNGRDEEQYI 1354
<210>10
<211>573
<212>DNA
<213> drosophila melanogaster (Drosophila melanogaster)
<400>10
atggatcattcccaccatatggggatgagctatatggactccaacagtaccatgcaacct 60
tctcaccatcacccaaccacttcagcctcacactcccatggtggaggagacagcagcatg 120
atgatgatgcctatgaccttctactttggctttaagaatgtggaactactgttttccggt 180
ttggtgatcaatacagctggagaaatggctggagcttttgtggcagtgtttttactagca 240
atgttctatgaaggactcaagatagcccgagagagcctgctgcgtaagtcacaagtcagc 300
attcgctacaattccatgcctgtcccaggaccaaatggaaccatccttatggagacacac 360
aaaactgttgggcaacagatgctgagctttcctcacctcctgcaaacagtgctgcacatc 420
atccaggtggtcataagctacttcctcatgctcatcttcatgacctacaacgggtacctc 480
tgcattgcagtagcagcaggggccggtacaggatacttcctcttcagctggaagaaggca 540
gtggtagtggatatcacagagcattgccattga 573
<210>11
<211>4503
<212>DNA
<213> drosophila melanogaster (Drosophila melanogaster)
<400>11
atggatccaagtatgggtgtgaattctgttaccatttctgttgagggtatgacttgcaat 60
tcctgtgtttggaccattgagcagcagattggaaaagtgaatggtgtgcatcacattaag 120
gtatcactggaagaaaaaaatgcaactattatttatgaccctaaactacagactccaaag 180
accctacaggaagctattgatgacatgggctttgatgctgttatccataatcctgaccct 240
ctccctgttttaactgacaccttgtttctgactgttacggcgtcactgactttgccatgg 300
gaccatatccaaagcacattgctgaagaccaagggtgtgacagacattaaaatttaccct 360
cagaaaagaactgtagcagtgacaataatcccttctatagtgaatgccaatcagataaaa 420
gagctggttccagaactcagtttagatactgggacactggagaaaaagtcaggagcttgt 480
gaagatcatagtatggctcaagctggtgaagtcgtgctgaagatgaaagtggaagggatg 540
acctgccattcatgtactagcactattgaaggaaaaattgggaaactgcaaggtgttcag 600
cgaattaaagtctccctggacaatcaagaagctactattgtttatcaacctcatcttatc 660
tcagtagaggaaatgaaaaagcagattgaagctatgggctttccagcatttgtcaaaaag 720
cagcccaagtacctcaaattgggagctattgatgtagaacgtctaaagaacacaccagtt 780
aaatcctcagaagggtcacagcaaaggagtccatcatataccaatgattcaacagccact 840
ttcatcattgatggcatgcattgtaaatcatgtgtgtcaaatattgaaagtactttatct 900
gcactccaatatgtaagcagcatagtagtttctttagagaataggtctgccattgtgaag 960
tataatgcaagctcagtcactccagaatccctgagaaaagcaatagaggctgtatcaccg 1020
gggctatatagagttagtatcacaagtgaagttgagagtacctcaaactctccctccagc 1080
tcatctcttcagaagattcctttgaatgtagttagccagcctctgacacaagaaactgtg 1140
ataaacattgatggcatgacttgtaattcctgtgtgcagtctattgagggtgtcatatca 1200
aaaaagccaggtgtaaaatccatacgagtctcccttgcaaatagcaatgggactgttgag 1260
tatgatcctctactaacctctccagaaacgttgagaggagcaatagaagacatgggattt 1320
gatgctaccttgtcagacacgaatgagccgttggtagtaatagctcagccttcatcggaa 1380
atgccgcttttgacttcaactaatgaattttatactaaagggatgacaccagttcaagac 1440
aaggaggaaggaaagaattcatctaagtgttacatacaggtcactggcatgacttgcgct 1500
tcctgtgtagcaaacattgaacggaatttaaggcgggaagaaggaatatattctatactt 1560
gtggccctgatggctggcaaggcagaagtaaggtataatcctgctgttatacaaccccca 1620
atgatagcagagttcatccgagaacttggatttggagccactgtgatagaaaatgctgat 1680
gaaggagatggtgttttggaacttgttgtgaggggaatgacgtgtgcctcctgcgtacat 1740
aaaatagagtctagtctcacaaaacacagagggatcctatactgctccgtggccctggca 1800
accaacaaagcacatattaaatatgacccagaaattattggtcctagagatattatccat 1860
acaattgaaagcttaggttttgaagcttctttggtcaagaaggatcggtcagcaagtcac 1920
ttagatcataaacgagaaataagacaatggagacggtcttttcttgtgagtctgtttttc 1980
tgtattcctgtaatggggctgatgatatatatgatggttatggaccaccactttgcaact 2040
cttcaccataatcaaaacatgagtaaagaagaaatgatcaaccttcattcttctatgttc 2100
ctggagcgccagattcttccaggattgtctgttatgaatttgctgtcctttttattgtgt 2160
gtacctgtacagtttttcggaggctggtacttctacattcaggcttataaagcactgaag 2220
cataagacagcaaatatggacgtactgattgtgctggcaaccaccattgcatttgcctac 2280
tctttgattattcttctagttgcaatgtatgagagagccaaagtgaaccctattactttc 2340
tttgacacaccccctatgctgtttgtgtttattgcactaggccgatggctggaacatata 2400
gcaaagggcaaaacatcagaggctcttgcaaagttaatttcactacaagctacagaagca 2460
actattgtaactcttgattctgataatatcctcctcagtgaagaacaagtggatgtggaa 2520
cttgtacaacgtggagatatcattaaagtagttccaggaggcaaatttccagtggatggt 2580
cgtgttattgaaggacattctatggtagatgagtccctcatcacaggggaggcaatgcct 2640
gtggctaagaaacctggcagcacagtgattgctggttccattaaccagaacgggtcactg 2700
cttatctgcgcaacacatgttggagcagacacaaccctttctcaaattgtcaaacttgtg 2760
gaagaggcacaaacatcaaaggctcctatccagcagtttgcagacaaactcagtggctat 2820
tttgttccttttattgtttttgtttccattgccaccctcttggtatggattgtaattgga 2880
tttctgaattttgaaattgtggaaacctactttcctggctacaatagaagtatctcccga 2940
acagaaacgataatacgatttgctttccaagcctctatcacagttctgtgtattgcatgt 3000
ccctgttcactgggactggccactccaactgctgtgatggtgggtacaggagtaggtgct 3060
caaaatggcatactaataaaaggtggagagccattggagatggctcataaggtaaaggta 3120
gtggtatttgataagactggaaccattactcacggaaccccagtggtgaatcaagtaaag 3180
gttctaactgaaagtaacagaatatcacaccataaaatcttggccattgtgggaactgct 3240
gaaagtaacagtgaacaccctctaggaacagccataaccaaatattgcaaacaggagctg 3300
gacactgaaaccttgggtacctgcatagatttccaggttgtgccaggctgtggtattagc 3360
tgtaaagtcaccaatattgaaggcttgctacataagaataactggaatatagaggacaat 3420
aatattaaaaatgcatccctggttcaaattgatgccagtaatgaacagtcatcaacttcg 3480
tcttccatgattattgatgcccagatctcaaatgctcttaatgctcagcagtataaagtc 3540
ctcattggtaaccgggagtggatgattagaaatggtcttgtcattaataacgatgtaaat 3600
gatttcatgactgaacatgagagaaaaggtcggactgctgtattagtagcagttgatgat 3660
gagctgtgtggcttgatagccattgcagacacagtgaagcctgaagcagaactggctatc 3720
catattctgaaatctatgggcttagaagtagttctgatgactggagacaacagtaaaaca 3780
gctagatctattgcttctcaggttggcattactaaggtgtttgctgaagttctaccttct 3840
cacaaggttgctaaagtgaagcaacttcaagaggaggggaaacgggtagcaatggtggga 3900
gatggaatcaatgactccccagctctggcaatggctaatgtgggaattgctattggcaca 3960
ggcacagatgtagccattgaagcagctgatgtggttttgataaggaatgatcttctggat 4020
gtagtggcaagtattgacttatcaagagagacagtcaagaggattcggataaattttgtc 4080
tttgctctaatttataatctggttggaattcccatagctgctggagtttttatgcccatt 4140
ggtttggttttgcagccctggatgggatctgcagcaatggctgcttcatctgtttctgta 4200
gtactttcttctctcttccttaaactttacaggaaaccaacttacgagagttatgaactg 4260
cctgcccggagccagataggacagaagagtccttcagaaatcagcgttcatgttggaata 4320
gatgatacctcaaggaattctcctaaactgggtttgctggaccggattgttaattatagc 4380
agagcctctataaactcactactgtctgataaacgctccctaaacagtgttgttaccagt 4440
gaacctgacaagcactcactcctggtgggagacttcagggaagatgatgacactgcatta 4500
taa 4503
<210>12
<211>4398
<212>DNA
<213> drosophila melanogaster (Drosophila melanogaster)
<400>12
atgcctgagcaggagagacagatcacagccagagaaggggccagtcggaaaatcttatct 60
aagctttctttgcctacccgtgcctgggaaccagcaatgaagaagagttttgcttttgac 120
aatgttggctatgaaggtggtctggatggcctgggcccttcttctcaggtggccaccagc 180
acagtcaggatcttgggcatgacttgccagtcatgtgtgaagtccattgaggacaggatt 240
tccaatttgaaaggcatcatcagcatgaaggtttccctggaacaaggcagtgccactgtg 300
aaatatgtgccatcggttgtgtgcctgcaacaggtttgccatcaaattggggacatgggc 360
ttcgaggccagcattgcagaaggaaaggcagcctcctggccctcaaggtccttgcctgcc 420
caggaggctgtggtcaagctccgggtggagggcatgacctgccagtcctgtgtcagctcc 480
attgaaggcaaggtccggaaactgcaaggagtagtgagagtcaaagtctcactcagcaac 540
caagaggccgtcatcacttatcagccttatctcattcagcccgaagacctcagggaccat 600
gtaaatgacatgggatttgaagctgccatcaagagcaaagtggctcccttaagcctggga 660
ccaattgatattgagcggttacaaagcactaacccaaagagacctttatcttctgctaac 720
cagaattttaataattctgagaccttggggcaccaaggaagccatgtggtcaccctccaa 780
ctgagaatagatggaatgcattgtaagtcttgcgtcttgaatattgaagaaaatattggc 840
cagctcctaggggttcaaagtattcaagtgtccttggagaacaaaactgcccaagtaaag 900
tatgacccttcttgtaccagcccagtggctctgcagagggctatcgaggcacttccacct 960
gggaattttaaagtttctcttcctgatggagccgaagggagtgggacagatcacaggtct 1020
tccagttctcattcccctggctccccaccgagaaaccaggtccagggcacatgcagtacc 1080
actctgattgccattgccggcatgacctgtgcatcctgtgtccattccattgaaggcatg 1140
atctcccaactggaaggggtgcagcaaatatcggtgtctttggccgaagggactgcaaca 1200
gttctttataatccctctgtaattagcccagaagaactcagagctgctatagaagacatg 1260
ggatttgaggcttcagtcgtttctgaaagctgttctactaaccctcttggaaaccacagt 1320
gctgggaattccatggtgcaaactacagatggtacacctacatctgtgcaggaagtggct 1380
ccccacactgggaggctccctgcaaaccatgccccggacatcttggcaaagtccccacaa 1440
tcaaccagagcagtggcaccgcagaagtgcttcttacagatcaaaggcatgacctgtgca 1500
tcctgtgtgtctaacatagaaaggaatctgcagaaagaagctggtgttctctccgtgttg 1560
gttgccttgatggcaggaaaggcagagatcaagtatgacccagaggtcatccagcccctc 1620
gagatagctcagttcatccaggacctgggttttgaggcagcagtcatggaggactacgca 1680
ggctccgatggcaacattgagctgacaatcacagggatgacctgcgcgtcctgtgtccac 1740
aacatagagtccaaactcacgaggacaaatggcatcacttatgcctccgttgcccttgcc 1800
accagcaaagcccttgttaagtttgacccggaaattatcggtccacgggatattatcaaa 1860
attattgaggaaattggctttcatgcttccctggcccagagaaaccccaacgctcatcac 1920
ttggaccacaagatggaaataaagcagtggaagaagtctttcctgtgcagcctggtgttt 1980
ggcatccctgtcatggccttaatgatctatatgctgatacccagcaacgagccccaccag 2040
tccatggtcctggaccacaacatcattccaggactgtccattctaaatctcatcttcttt 2100
atcttgtgtacctttgtccagctcctcggtgggtggtacttctacgttcaggcctacaaa 2160
tctctgagacacaggtcagccaacatggacgtgctcatcgtcctggccacaagcattgct 2220
tatgtttattctctggtcatcctggtggttgctgtggctgagaaggcggagaggagccct 2280
gtgacattcttcgacacgccccccatgctctttgtgttcattgccctgggccggtggctg 2340
gaacacttggcaaagagcaaaacctcagaagccctggctaaactcatgtctctccaagcc 2400
acagaagccaccgttgtgacccttggtgaggacaatttaatcatcagggaggagcaagtc 2460
cccatggagctggtgcagcggggcgatatcgtcaaggtggtccctgggggaaagtttcca 2520
gtggatgggaaagtcctggaaggcaataccatggctgatgagtccctcatcacaggagaa 2580
gccatgccagtcactaagaaacccggaagcactgtaattgcggggtctataaatgcacat 2640
ggctctgtgctcattaaagctacccacgtgggcaatgacaccactttggctcagattgtg 2700
aaactggtggaagaggctcagatgtcaaaggcacccattcagcagctggctgaccggttt 2760
agtggatattttgtcccatttatcatcatcatgtcaactttgacgttggtggtatggatt 2820
gtaatcggttttatcgattttggtgttgttcagagatactttcctaaccccaacaagcac 2880
atctcccagacagaggtgatcatccggtttgctttccagacgtccatcacggtgctgtgc 2940
attgcctgcccctgctccctggggctggccacgcccacggctgtcatggtgggcaccggg 3000
gtggccgcgcagaacggcatcctcatcaagggaggcaagcccctggagatggcgcacaag 3060
ataaagactgtgatgtttgacaagactggcaccattacccatggcgtccccagggtcatg 3120
cgggtgctcctgctgggggatgtggccacactgcccctcaggaaggttctggctgtggtg 3180
gggactgcggaggccagcagtgaacaccccttgggcgtggcagtcaccaaatactgtaaa 3240
gaggaacttggaacagagaccttgggatactgcacggacttccaggcagtgccaggctgt 3300
ggaattgggtgcaaagtcagcaacgtggaaggcatcctggcccacagtgagcgccctttg 3360
agtgcaccggccagtcacctgaatgaggctggcagccttcccgcagaaaaagatgcagtc 3420
ccccagaccttctctgtgctgattggaaaccgtgagtggctgaggcgcaacggtttaacc 3480
atttctagcgatgtcagtgacgctatgacagaccacgagatgaaaggacagacagccatc 3540
ctggtggctattgacggtgtgctctgtgggatgatcgcaatcgcagacgctgtcaagcag 3600
gaggctgccctggctgtgcacacgctgcagagcatgggtgtggacgtggttctgatcacg 3660
ggggacaaccggaagacagccagagctattgccacccaggttggcatcaacaaagtcttt 3720
gcagaggtgctgccttcgcacaaggtggccaaggtccaggagctccagaataaagggaag 3780
aaagtcgccatggtgggggatggggtcaatgactccccggccttggcccaggcagacatg 3840
ggtgtggccattggcaccggcacggatgtggccatcgaggcagccgacgtcgtccttatc 3900
agaaatgatttgctggatgtggtggctagcattcacctttccaagaggactgtccgaagg 3960
atacgcatcaacctggtcctggcactgatttataacctggttgggatacccattgcagca 4020
ggtgtcttcatgcccatcggcattgtgctgcagccctggatgggctcagcggccatggca 4080
gcctcctctgtgtctgtggtgctctcatccctgcagctcaagtgctataagaagcctgac 4140
ctggagaggtatgaggcacaggcgcatggccacatgaagcccctgacggcatcccaggtc 4200
agtgtgcacataggcatggatgacaggtggcgggactcccccagggccacaccatgggac 4260
caggtcagctatgtcagccaggtgtcgctgtcctccctgacgtccgacaagccatctcgg 4320
cacagcgctgcagcagacgatgatggggacaagtggtctctgctcctgaatggcagggat 4380
gaggagcagtacatctga 4398
<210>13
<211>3777
<212>DNA
<213> drosophila melanogaster (Drosophila melanogaster)
<400>13
atgcctgagcaggagagacagatcacagccagagaaggggccagtcggaaaatcttatct 60
aagctttctttgcctacccgtgcctgggaaccagcaatgaagaagagttttgcttttgac 120
aatgttggctatgaaggtggtctggatggcctgggcccttcttctcaggtggccaccagc 180
acagtcaggatcttgggcatgacttgccagtcatgtgtgaagtccattgaggacaggatt 240
tccaatttgaaaggcatcatcagcatgaaggtttccctggaacaaggcagtgccactgtg 300
aaatatgtgccatcggttgtgtgcctgcaacaggtttgccatcaaattggggacatgggc 360
ttcgaggccagcattgcagaaggaaaggcagcctcctggccctcaaggtccttgcctgcc 420
caggaggctgtggtcaagctccgggtggagggcatgacctgccagtcctgtgtcagctcc 480
attgaaggcaaggtccggaaactgcaaggagtagtgagagtcaaagtctcactcagcaac 540
caagaggccgtcatcacttatcagccttatctcattcagcccgaagacctcagggaccat 600
gtaaatgacatgggatttgaagctgccatcaagagcaaagtggctcccttaagcctggga 660
ccaattgatattgagcggttacaaagcactaacccaaagagacctttatcttctgctaac 720
cagaattttaataattctgagaccttggggcaccaaggaagccatgtggtcaccctccaa 780
ctgagaatagatggaatgcattgtaagtcttgcgtcttgaatattgaagaaaatattggc 840
cagctcctaggggttcaaagtattcaagtgtccttggagaacaaaactgcccaagtaaag 900
tatgacccttcttgtaccagcccagtggctctgcagagggctatcgaggcacttccacct 960
gggaattttaaagtttctcttcctgatggagccgaagggagtgggacagatcacaggtct 1020
tccagttctcattcccctggctccccaccgagaaaccaggtccagggcacatgcagtacc 1080
actctgattgccattgccggcatgacctgtgcatcctgtgtccattccattgaaggcatg 1140
atctcccaactggaaggggtgcagcaaatatcggtgtctttggccgaagggactgcaaca 1200
gttctttataatccctctgtaattagcccagaagaactcagagctgctatagaagacatg 1260
ggatttgaggcttcagtcgtttctgaaagctgttctactaaccctcttggaaaccacagt 1320
gctgggaattccatggtgcaaactacagatggtacacctacatctgtgcaggaagtggct 1380
ccccacactgggaggctccctgcaaaccatgccccggacatcttggcaaagtccccacaa 1440
tcaaccagagcagtggcaccgcagaagtgcttcttacagatcaaaggcatgacctgtgca 1500
tcctgtgtgtctaacatagaaaggaatctgcagaaagaagctggtgttctctccgtgttg 1560
gttgccttgatggcaggaaaggcagagatcaagtatgacccagaggtcatccagcccctc 1620
gagatagctcagttcatccaggacctgggttttgaggcagcagtcatggaggactacgca 1680
ggctccgatggcaacattgagctgacaatcacagggatgacctgcgcgtcctgtgtccac 1740
aacatagagtccaaactcacgaggacaaatggcatcacttatgcctccgttgcccttgcc 1800
accagcaaagcccttgttaagtttgacccggaaattatcggtccacgggatattatcaaa 1860
attattgagagcaaaacctcagaagccctggctaaactcatgtctctccaagccacagaa 1920
gccaccgttgtgacccttggtgaggacaatttaatcatcagggaggagcaagtccccatg 1980
gagctggtgcagcggggcgatatcgtcaaggtggtccctgggggaaagtttccagtggat 2040
gggaaagtcctggaaggcaataccatggctgatgagtccctcatcacaggagaagccatg 2100
ccagtcactaagaaacccggaagcactgtaattgcggggtctataaatgcacatggctct 2160
gtgctcattaaagctacccacgtgggcaatgacaccactttggctcagattgtgaaactg 2220
gtggaagaggctcagatgtcaaagaaccccaacaagcacatctcccagacagaggtgatc 2280
atccggtttgctttccagacgtccatcacggtgctgtgcattgcctgcccctgctccctg 2340
gggctggccacgcccacggctgtcatggtgggcaccggggtggccgcgcagaacggcatc 2400
ctcatcaagggaggcaagcccctggagatggcgcacaagataaagactgtgatgtttgac 2460
aagactggcaccattacccatggcgtccccagggtcatgcgggtgctcctgctgggggat 2520
gtggccacactgcccctcaggaaggttctggctgtggtggggactgcggaggccagcagt 2580
gaacaccccttgggcgtggcagtcaccaaatactgtaaagaggaacttggaacagagacc 2640
ttgggatactgcacggacttccaggcagtgccaggctgtggaattgggtgcaaagtcagc 2700
aacgtggaaggcatcctggcccacagtgagcgccctttgagtgcaccggccagtcacctg 2760
aatgaggctggcagccttcccgcagaaaaagatgcagtcccccagaccttctctgtgctg 2820
attggaaaccgtgagtggctgaggcgcaacggtttaaccatttctagcgatgtcagtgac 2880
gctatgacagaccacgagatgaaaggacagacagccatcctggtggctattgacggtgtg 2940
ctctgtgggatgatcgcaatcgcagacgctgtcaagcaggaggctgccctggctgtgcac 3000
acgctgcagagcatgggtgtggacgtggttctgatcacgggggacaaccggaagacagcc 3060
agagctattgccacccaggttggcatcaacaaagtctttgcagaggtgctgccttcgcac 3120
aaggtggccaaggtccaggagctccagaataaagggaagaaagtcgccatggtgggggat 3180
ggggtcaatgactccccggccttggcccaggcagacatgggtgtggccattggcaccggc 3240
acggatgtggccatcgaggcagccgacgtcgtccttatcagaaatgatttgctggatgtg 3300
gtggctagcattcacctttccaagaggactgtccgaaggatacgcatcaacctggtcctg 3360
gcactgatttataacctggttgggatacccattgcagcaggtgtcttcatgcccatcggc 3420
attgtgctgcagccctggatgggctcagcggccatggcagcctcctctgtgtctgtggtg 3480
ctctcatccctgcagctcaagtgctataagaagcctgacctggagaggtatgaggcacag 3540
gcgcatggccacatgaagcccctgacggcatcccaggtcagtgtgcacataggcatggat 3600
gacaggtggcgggactcccccagggccacaccatgggaccaggtcagctatgtcagccag 3660
gtgtcgctgtcctccctgacgtccgacaagccatctcggcacagcgctgcagcagacgat 3720
gatggggacaagtggtctctgctcctgaatggcagggatgaggagcagtacatctga 3777
<210>14
<211>4065
<212>DNA
<213> drosophila melanogaster (Drosophila melanogaster)
<400>14
atgcctgagcaggagagacagatcacagccagagaaggggccagtcggaaaatcttatct 60
aagctttctttgcctacccgtgcctgggaaccagcaatgaagaagagttttgcttttgac 120
aatgttggctatgaaggtggtctggatggcctgggcccttcttctcaggtggccaccagc 180
acagtcaggatcttgggcatgacttgccagtcatgtgtgaagtccattgaggacaggatt 240
tccaatttgaaaggcatcatcagcatgaaggtttccctggaacaaggcagtgccactgtg 300
aaatatgtgccatcggttgtgtgcctgcaacaggtttgccatcaaattggggacatgggc 360
ttcgaggccagcattgcagaaggaaaggcagcctcctggccctcaaggtccttgcctgcc 420
caggaggctgtggtcaagctccgggtggagggcatgacctgccagtcctgtgtcagctcc 480
attgaaggcaaggtccggaaactgcaaggagtagtgagagtcaaagtctcactcagcaac 540
caagaggccgtcatcacttatcagccttatctcattcagcccgaagacctcagggaccat 600
gtaaatgacatgggatttgaagctgccatcaagagcaaagtggctcccttaagcctggga 660
ccaattgatattgagcggttacaaagcactaacccaaagagacctttatcttctgctaac 720
cagaattttaataattctgagaccttggggcaccaaggaagccatgtggtcaccctccaa 780
ctgagaatagatggaatgcattgcatgatctcccaactggaaggggtgcagcaaatatcg 840
gtgtctttggccgaagggactgcaacagttctttataatccctctgtaattagcccagaa 900
gaactcagagctgctatagaagacatgggatttgaggcttcagtcgtttctgaaagctgt 960
tctactaaccctcttggaaaccacagtgctgggaattccatggtgcaaactacagatggt 1020
acacctacatctgtgcaggaagtggctccccacactgggaggctccctgcaaaccatgcc 1080
ccggacatcttggcaaagtccccacaatcaaccagagcagtggcaccgcagaagtgcttc 1140
ttacagatcaaaggcatgacctgtgcatcctgtgtgtctaacatagaaaggaatctgcag 1200
aaagaagctggtgttctctccgtgttggttgccttgatggcaggaaaggcagagatcaag 1260
tatgacccagaggtcatccagcccctcgagatagctcagttcatccaggacctgggtttt 1320
gaggcagcagtcatggaggactacgcaggctccgatggcaacattgagctgacaatcaca 1380
gggatgacctgcgcgtcctgtgtccacaacatagagtccaaactcacgaggacaaatggc 1440
atcacttatgcctccgttgcccttgccaccagcaaagcccttgttaagtttgacccggaa 1500
attatcggtccacgggatattatcaaaattattgaggaaattggctttcatgcttccctg 1560
gcccagagaaaccccaacgctcatcacttggaccacaagatggaaataaagcagtggaag 1620
aagtctttcctgtgcagcctggtgtttggcatccctgtcatggccttaatgatctatatg 1680
ctgatacccagcaacgagccccaccagtccatggtcctggaccacaacatcattccagga 1740
ctgtccattctaaatctcatcttctttatcttgtgtacctttgtccagctcctcggtggg 1800
tggtacttctacgttcaggcctacaaatctctgagacacaggtcagccaacatggacgtg 1860
ctcatcgtcctggccacaagcattgcttatgtttattctctggtcatcctggtggttgct 1920
gtggctgagaaggcggagaggagccctgtgacattcttcgacacgccccccatgctcttt 1980
gtgttcattgccctgggccggtggctggaacacttggcaaagagcaaaacctcagaagcc 2040
ctggctaaactcatgtctctccaagccacagaagccaccgttgtgacccttggtgaggac 2100
aatttaatcatcagggaggagcaagtccccatggagctggtgcagcggggcgatatcgtc 2160
aaggtggtccctgggggaaagtttccagtggatgggaaagtcctggaaggcaataccatg 2220
gctgatgagtccctcatcacaggagaagccatgccagtcactaagaaacccggaagcact 2280
gtaattgcggggtctataaatgcacatggctctgtgctcattaaagctacccacgtgggc 2340
aatgacaccactttggctcagattgtgaaactggtggaagaggctcagatgtcaaaggca 2400
cccattcagcagctggctgaccggtttagtggatattttgtcccatttatcatcatcatg 2460
tcaactttgacgttggtggtatggattgtaatcggttttatcgattttggtgttgttcag 2520
agatactttcctaaccccaacaagcacatctcccagacagaggtgatcatccggtttgct 2580
ttccagacgtccatcacggtgctgtgcattgcctgcccctgctccctggggctggccacg 2640
cccacggctgtcatggtgggcaccggggtggccgcgcagaacggcatcctcatcaaggga 2700
ggcaagcccctggagatggcgcacaagataaagactgtgatgtttgacaagactggcacc 2760
attacccatggcgtccccagggtcatgcgggtgctcctgctgggggatgtggccacactg 2820
cccctcaggaaggttctggctgtggtggggactgcggaggccagcagtgaacaccccttg 2880
ggcgtggcagtcaccaaatactgtaaagaggaacttggaacagagaccttgggatactgc 2940
acggacttccaggcagtgccaggctgtggaattgggtgcaaagtcagcaacgtggaaggc 3000
atcctggcccacagtgagcgccctttgagtgcaccggccagtcacctgaatgaggctggc 3060
agccttcccgcagaaaaagatgcagtcccccagaccttctctgtgctgattggaaaccgt 3120
gagtggctgaggcgcaacggtttaaccatttctagcgatgtcagtgacgctatgacagac 3180
cacgagatgaaaggacagacagccatcctggtggctattgacggtgtgctctgtgggatg 3240
atcgcaatcgcagacgctgtcaagcaggaggctgccctggctgtgcacacgctgcagagc 3300
atgggtgtggacgtggttctgatcacgggggacaaccggaagacagccagagctattgcc 3360
acccaggttggcatcaacaaagtctttgcagaggtgctgccttcgcacaaggtggccaag 3420
gtccaggagctccagaataaagggaagaaagtcgccatggtgggggatggggtcaatgac 3480
tccccggccttggcccaggcagacatgggtgtggccattggcaccggcacggatgtggcc 3540
atcgaggcagccgacgtcgtccttatcagaaatgatttgctggatgtggtggctagcatt 3600
cacctttccaagaggactgtccgaaggatacgcatcaacctggtcctggcactgatttat 3660
aacctggttgggatacccattgcagcaggtgtcttcatgcccatcggcattgtgctgcag 3720
ccctggatgggctcagcggccatggcagcctcctctgtgtctgtggtgctctcatccctg 3780
cagctcaagtgctataagaagcctgacctggagaggtatgaggcacaggcgcatggccac 3840
atgaagcccctgacggcatcccaggtcagtgtgcacataggcatggatgacaggtggcgg 3900
gactcccccagggccacaccatgggaccaggtcagctatgtcagccaggtgtcgctgtcc 3960
tccctgacgtccgacaagccatctcggcacagcgctgcagcagacgatgatggggacaag 4020
tggtctctgctcctgaatggcagggatgaggagcagtacatctga 4065
Claims (1)
1. the application of RNAi interference carrier in the medicine for the preparation for the treatment of Huntington chorea of Target genes CtrlB, it is characterized in that, Target genes CtrlB nucleotide sequence is as shown in SEQ ID No.10.
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Non-Patent Citations (7)
| Title |
|---|
| Ctr1基因mRNA转录水平与细胞内铜离子浓度的相关性;付世新 等;《中国生物制品学杂志》;20100531(第5期);482-484 * |
| Distinct Mechanisms for Ctr1-mediated Copper and Cisplatin Transport;Devis Sinani et.al;《Journal of biological chemistry》;20070914;第282卷;26775-26785 * |
| Ethylene Regulates Arabidopsis Development via the Modulation of DELLA Protein Growth Repressor Function;Patrick Achard et.al;《The Plant Cell》;20031231;第15卷(第12期);2816-2825 * |
| Genbank accession No:NM_001859.3;NCBI;《Genbank》;20120417;全序列 * |
| Genbank accession No:NP_001850.1;NCBI;《Genbank》;20121209;全序列 * |
| Mechanisms of copper ion mediated Huntington’s disease progression;Jonathan H.Fox et.al;《PLOS ONE》;20070831;第2卷(第3期);1-12 * |
| 黄云鹏 等.利用黑腹果蝇(Drosophila melanogaster)研究微量金属元素代谢.《生命科学》.2012,第24卷(第8期),927-938. * |
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