CN103937804A - Congenital aniridia disease-causing gene, kit for detecting congenital aniridia disease-causing gene and application of gene - Google Patents
Congenital aniridia disease-causing gene, kit for detecting congenital aniridia disease-causing gene and application of gene Download PDFInfo
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Abstract
The invention discloses a congenital aniridia disease-causing gene, a kit for detecting the congenital aniridia disease-causing gene and an application of the gene. The congenital aniridia disease-causing gene is a mutational PAX6 (Paired box6) gene, one point of a basic group in a 323th site of a sixth exon of the PAX6 gene is muted to A from C, and a genetic codon (TCC) for encoding serine at a 108th site is changed into a genetic codon (TAC) for encoding tyrosine, namely S108Y mutation is caused. The invention also provides a kit used for detecting the congenital aniridia disease-causing gene. The kit used for detecting the congenital aniridia disease-causing gene comprises 2mM dNTPs, 10*PCR (Polymerase Chain Reaction) buffer solution, DNA polymerase, PCR amplification primer pairs and double distilled water, wherein the PCR amplification primer pair is composed of a primer 1 (shown in SEQ ID NO:1) and a primer 2 (shown in SEQ ID NO:2). The invention provides a new congenital aniridia disease-causing gene, so that a new technological means is provided for genetic diagnosis of congenital aniridia, and a foundation is also laid for study of a pathogenetic molecular mechanism.
Description
Technical field
What the present invention relates to is a kind of gene detecting kit and application thereof, specifically relates to a kind of congenital aniridia disease Disease-causing gene detection kit and application thereof.The invention belongs to disease detection and diagnostic techniques field.
Background technology
Irideremia disease is eyes developmental character illness, principal character be lacking of congenital hypoplasia of iris or normal iris as, also can, with multiple eye illness, as corneal clouding, microcornea, lens-dislocation, cataract, hypoplasia of macula, stravismus, ocular ataxy etc., involve whole eyeball.
Due to iridocoloboma degree difference, therefore clinical manifestation differs, but there is photophobia, frown and the performance such as blink, weak-eyed also may carrying out property go down.Some is suffered from eye torch light or just can see remaining peripheral iris in the time of slit lamp examination clinically, and some can only just can see remaining iris root tissue under gonioscope.More patient just has periphery corneal pannus and corneal clouding in early days, is developed to gradually cornea central part with age growth.Occasionally there is the situation of microcornea, sclerosis of cornea disease and cornea and lens adhesion.Lens heteroplasia is muddy as common taking congenital limitation lens, also can Phakic dystopy or congenital defect, and there is progressive cataract and can make eyesight obviously go down.That irideremia also can associated with choroidal is damaged, persistent pupillary membrane, little optic disk, stravismus and ptosis etc., as the dysplasia at companion macula lutea center can cause ocular ataxy.Irideremia patient is when with glaucoma, and residual iris covers forward trabecular network gradually, once function girder is blocked, intraocular pressure will raise gradually, and glaucomatous severity is relevant with goniosynechia situation.
Congenital aniridia disease men and women both sexes morbidity is identical, can isolate generation, can merge other eye heteroplasia, or a part for heredity multisystem syndromes.Approximately having 2/3 irideremia patient to have family history, is autosomal dominant inheritance; 1/3 patient is sporadic, mostly is recessive inheritance.Its hereditary basis and pathogenesis are still not fully aware of.It is the important step of understanding the molecular mechanism of its morbidity that the sudden change of congenital aniridia disease Disease-causing gene is detected.
Summary of the invention
One of object of the present invention is to provide a kind of new congenital aniridia disease Disease-causing gene;
Two of object of the present invention is to provide described congenital aniridia disease Disease-causing gene in preparation diagnosis or detects the application in congenital aniridia disease reagent;
Three of object of the present invention is to provide a kind of test kit that above-mentioned congenital aniridia disease Disease-causing gene detects that can be used for;
Four of object of the present invention is to provide described test kit in preparation diagnosis or detects the application in congenital aniridia disease reagent.
The object of the invention is to be achieved through the following technical solutions:
A kind of congenital aniridia disease Disease-causing gene of the present invention, it is characterized in that described Disease-causing gene is the PAX6 gene (Paired box6) of sudden change, the 323rd bit base (using first Nucleotide of cDNA as 1 calculating) of the 6th exon of this PAX6 gene, has the point mutation of a C->A.
The gDNA Gene Bank accession number of this PAX6 gene is NC_000011, and the Gene Bank accession number of cDNA is NM_001604, and the Gene Bank accession number of corresponding protein is NP_001595.
The nucleotide sequence of the 6th exon of the PAX6 gene before sudden change is as shown in SEQ ID NO:3, and the nucleotide sequence of the 6th exon of the PAX6 gene after sudden change is as shown in SEQ ID NO:4.
This sudden change cause encoding genetic codon (TCC) of the 108th Serine becomes the genetic codon (TAC) of tyrosine, and S108Y sudden change has occurred.
Further, the invention allows for described congenital aniridia disease Disease-causing gene in preparation diagnosis or detect the application in congenital aniridia disease reagent.
A kind of test kit detecting for congenital aniridia disease Disease-causing gene of the present invention, comprise: 2mM dNTPs, 10 × PCR reaction buffer, archaeal dna polymerase, pcr amplification primer to and distilled water, it is characterized in that: described pcr amplification primer is to being made up of primer 1 and primer 2, wherein, the nucleotides sequence of primer 1 is classified as: shown in CGTAAGCTTGTCATTGTTTAATGC(SEQ ID NO:1), the nucleotides sequence of primer 2 is classified as shown in AGAGAGGGTGGGAGGAGGTA(SEQ ID NO:2).
This test kit is for the amplification of congenital aniridia disease Disease-causing gene, and it adopts Touch-down PCR to increase, and response procedures is:
95 DEG C of denaturations 2 minutes, then enter first circulation, 95 DEG C of sex change 40 seconds, 63 DEG C of annealing renaturation 30 seconds, 72 DEG C are extended 1min, and every circulation primary reduces by 0.5 DEG C afterwards, carry out altogether 14 circulations, enter afterwards major cycle, 95 DEG C of sex change 40 seconds, 57 DEG C of annealing renaturation 30 seconds, 72 DEG C are extended 1min, carry out altogether 25 circulations, and 72 DEG C are extended 10min, 4 DEG C of preservations, shown in table 2.
Further, the invention allows for described a kind of congenital aniridia disease Disease-causing gene detection kit in preparation diagnosis or detect the application in congenital aniridia disease reagent.
Utilize test kit of the present invention to detect a method for congenital aniridia disease Disease-causing gene, comprise the following steps:
(1) use the QIAamp DNA Blood Mini Kit of QIAGEN company test kit extracting blood sample genomic dna;
(2) design primer:
Forward sequencing primer sequence is: shown in CGTAAGCTTGTCATTGTTTAATGC(SEQ ID NO:1);
Reverse sequencing primer sequence is: shown in AGAGAGGGTGGGAGGAGGTA(SEQ ID NO:2);
(3) sample DNA target fragment is carried out to PCR amplification in vitro;
PCR system is as shown in table 1:
Table 1
PCR reaction is carried out on 9700PCR instrument, and PCR response procedures is shown in table 2:
Table 2
PCR product electrophoresis detection:
After PCR reaction finishes, get 2 × Loading Buffer that 2 μ l reaction product add 2 μ l, centrifugal 30 seconds of 4000rpm, is splined in 1.5% sepharose electrophoresis 15min under 100V voltage, gel video camera shot detection;
(4) PCR product is carried out to purifying
Adopt the SAP remaining dNTP that degrades, the Exo remaining primer of degrading, is pre-mixed rear preservation by SAP and two kinds of enzymes of Exo and 10 × damping fluid, in every microlitre mixed solution containing SAP and each 0.5 unit of EXO, for each purification reaction, get PCR product 1.5-2 μ l and add SAP enzyme 1.5 μ l;
Response procedures is: SAP/Exo processes PCR product 40 minutes at 37 DEG C, and then 85 DEG C continue 20 minutes deactivation SAP/Exo enzymes, then 4 DEG C of insulations;
(5) PCR product is checked order
Sequencing reaction system is 5 μ l, comprises the PCR product after purifying, sequencing primer 3.2pmol and BDT0.5 μ l, remaining volume ddH
2o polishing,
Sequencing reaction program is shown in table 3:
Table 3
Detection method of the present invention can also comprise:
1, after sequencing reaction finishes, order-checking product purifying again, this purification step is as follows:
1) in 96 orifice plates of sequencing reaction, every hole adds 25 μ l sodium-acetate-ethanolic solns, i.e. 3M sodium-acetate+100% ethanol, and volume ratio is 1:25; 4 DEG C, centrifugal 45 minutes of 4000rpm; Be inverted, 600rpm dries for centrifugal 1 minute;
2) add again 50 μ l70% ethanolic solns; 4 DEG C, centrifugal 10 minutes of 4000rpm; Be inverted 600rpm dries for centrifugal 1 minute; Repeat once;
3) room temperature leaves standstill half an hour.
2, order-checking product, again before purifying, first carries out sex change to DNA sample, and the method for sex change is in the sample after purifying, to add 10 μ l HiDi, and on PCR instrument, 95 DEG C of maintenances make it complete sex change in 5 minutes, after sex change, at once put into ice at least 2 minutes.
In order to verify effect of the present invention, the present invention collects a congenital aniridia disease family.General physical checkup is visited or done in family member to get rid of Other diseases and system exception through investigation.Family member is carried out to detailed eye examination, comprised the fundoscopy after eyesight, slit-lamp microscope, mydriasis.All patients take pictures through slit-lamp microscope.The family member of all participation investigation and collected blood sample all understands the purpose and meaning of this research and has signed Informed Consent Form.This family is totally 4 generations, 36 family members, wherein patient 9 people.Patient clinical shows as intraocular iris and all lacks.Extract volunteer peripheric venous blood 5m1, after doing anti-freezing and process with EDTA ,-20 DEG C of Refrigerator stores.Gather in addition individual 100 people of normal Han nationality, gather peripheric venous blood 5ml, EDTA anti-freezing ,-20 DEG C of Refrigerator stores are as a control group.Its comparing result as depicted in figs. 1 and 2.
Two-way sequencing result shows PAX6 gene the 6th exon the 323rd bit base (using first Nucleotide of cDNA as 1 calculating) of congenital aniridia disease family, there is the point mutation of a C->A, the genetic codon (TCC) of the 108th Serine of causing encoding becomes the genetic codon (TAC) of tyrosine, and S108Y sudden change has occurred.The all irideremia diseases of family patient has identical point mutation, and interior all the other normal individuals of family and 100 normal controls all do not have this sudden change.Thereby having got rid of it is the possibility of rare SNP.Determine that PAX6 transgenation is the Disease-causing gene sudden change of this family.
Brief description of the drawings
Fig. 1 is family normal people forward sequencer map;
Fig. 2 is family patient forward sequencer map.
Embodiment
Further describe the present invention below in conjunction with specific embodiment, advantage and disadvantage of the present invention will be more clear along with description.But these embodiment are only exemplary, scope of the present invention are not formed to any restriction.It will be understood by those skilled in the art that lower without departing from the spirit and scope of the present invention and can the details of technical solution of the present invention and form be modified or be replaced, but these amendments and replacement all fall within the scope of protection of the present invention.
The preparation of 1 one kinds of test kits that detect for congenital aniridia disease Disease-causing gene of embodiment
1, the design of primer pair and synthetic
Shown in primer 1:CGTAAGCTTGTCATTGTTTAATGC(SEQ ID NO:1)
Primer 2: shown in AGAGAGGGTGGGAGGAGGTA(SEQ ID NO:2);
Employing automatic dna synthesizer is synthetic, and dilution is 20 μ mol/L.
2, the assembling of test kit
Comprise: 2mM dNTP, 10 × PCR reaction buffer, archaeal dna polymerase, pcr amplification primer to and distilled water.
2 one kinds of test kits that detect for congenital aniridia disease Disease-causing gene of embodiment are in the application of clinical detection
1, detect sample and experiment material:
Experiment material: genome DNA extracting reagent kit QIAamp DNA Blood Mini Kit is purchased from QIAGEN company; PCR detection kit is purchased from Qiagen, Hilden, Germany.
Detect sample: collect clinically a congenital aniridia disease family.General physical checkup is visited or done in family member to get rid of Other diseases and system exception through investigation.Family member is carried out to detailed eye examination, comprised the fundoscopy after eyesight, slit-lamp microscope, mydriasis.All patients take pictures through slit-lamp microscope.The family member of all participation investigation and collected blood sample all understands the purpose and meaning of this research and has signed Informed Consent Form.This family is totally 4 generations, 36 family members, wherein patient 9 people.Patient clinical shows as intraocular iris and all lacks.
2, detection method:
(1) use the genomic dna in the QIAamp DNA Blood Mini Kit of QIAGEN company test kit extracting family member blood sample;
(2) design primer:
Shown in primer 1:CGTAAGCTTGTCATTGTTTAATGC(SEQ ID NO:1)
Primer 2: shown in AGAGAGGGTGGGAGGAGGTA(SEQ ID NO:2);
(3) amplification in vitro of sample DNA target fragment (PCR)
PCR system is as follows:
First order-checking needs to be reacted and obtained sample DNA target fragment by PCR.Reaction system is as following table 1:
Table 1
PCR response procedures: adopt Touch-down PCR.
PCR reaction is carried out on 9700PCR instrument.PCR response procedures is as shown in table 2 below:
Table 2
PCR product electrophoresis detection
After PCR reaction finishes, get 2 × Loading Buffer that 2 μ l reaction product add 2 μ l, centrifugal 30 seconds of 4000rpm.Loading in 1.5% sepharose (5g Agarose, 100ml1 × TBE, 1.5 μ l10mg/ml EB), electrophoresis 15min under 100V voltage, gel video camera shot detection.
(4) PCR product purification
Primer and dNTP remaining in PCR product can produce detrimentally affect for follow-up sequencing reaction.We adopt SAP(arctic shrimp alkaline phosphatase) the remaining dNTP that degrades, Exo(exonuclease) the remaining primer of degrading.For ease of using, conventionally SAP and two kinds of enzymes of Exo and 10 × damping fluid are pre-mixed to rear preservation, in every microlitre mixed solution containing SAP and each 0.5 unit of EXO.
For each purification reaction, get PCR product 1.5-2 μ l and add SAP enzyme 1.5 μ l.
Response procedures is: SAP/Exo processes PCR product 40 minutes at 37 DEG C, and then 85 DEG C continue 20 minutes deactivation SAP/Exo enzymes, then 4 DEG C of insulations.
(5) PCR product is checked order
Sequencing reaction need to add sequencing primer and BDT(BigDye Terminator3.1, Applied Biosystems in the PCR product after purifying).Because object is the sudden change of screening Disease-causing gene, so we have carried out the two-way order-checking of forward and reverse primer.
Sequencing reaction system is 5 μ l, comprises the PCR product after purifying, sequencing primer 3.2pmol and BDT0.5 μ l, remaining volume ddH
2o polishing.
Sequencing reaction program is as shown in table 3 below.
Table 3
After sequencing reaction finishes, need to be to order-checking product purifying (purifying after order-checking) again, the small-molecule substance bringing to remove sequencing reaction, avoids its interference to order-checking.Purification step is as follows:
1) in 96 orifice plates of sequencing reaction, every hole adds 25 μ l sodium-acetate-ethanolic solns (3M sodium-acetate+100% ethanol, volume ratio is 1:25); 4 DEG C, centrifugal 45 minutes of 4000rpm; Be inverted, 600rpm dries for centrifugal 1 minute.
2) add again 50 μ l70% ethanolic solns; 4 DEG C, centrifugal 10 minutes of 4000rpm; Be inverted 600rpm dries for centrifugal 1 minute; Repeat once.
3) room temperature leaves standstill and allows its seasoning about half an hour.
Before order-checking, first to make the sex change of DNA sample.The method of sex change is in the sample after purifying, to add 10 μ l HiDi(deionized formamides), on PCR instrument, 95 DEG C keep making it for 5 minutes complete sex change.After sex change, at once put into ice and within least 2 minutes, prevent its renaturation.
Then loading to ABI PRISM3100 sequenator/somatotype instrument (Applied Biosystems) checks order.
3, result
Two-way sequencing result shows PAX6 gene the 6th exon the 323rd bit base of congenital aniridia disease family, there is the point mutation of a C->A, the nucleotide sequence of the 6th exon of the PAX6 gene before sudden change is as shown in SEQ ID NO:3, and the nucleotide sequence of the 6th exon of the PAX6 gene after sudden change is as shown in SEQ ID NO:4.The genetic codon (TCC) of the 108th Serine of causing encoding becomes the genetic codon (TAC) of tyrosine, and S108Y sudden change has occurred.The all irideremia diseases of family patient has identical point mutation, and interior all the other normal individuals of family and 100 normal controls all do not have this sudden change.Its comparing result as depicted in figs. 1 and 2.
Explanation thus, mutational site of the present invention is not rare SNP site.Also the C->A point mutation of having determined PAX6 gene the 323rd bit base is the Disease-causing gene sudden change of this family simultaneously.
Claims (5)
1. a congenital aniridia disease Disease-causing gene, is characterized in that described Disease-causing gene is the PAX6 gene (Paired box6) of sudden change, and the 323rd bit base of the 6th exon of this PAX6 gene, has the point mutation of a C->A.
2. the application of congenital aniridia disease Disease-causing gene claimed in claim 1 in preparation diagnosis or detection congenital aniridia disease reagent.
3. the test kit detecting for congenital aniridia disease Disease-causing gene, it is characterized in that this test kit comprises: 2mM dNTPs, 10 × PCR reaction buffer, archaeal dna polymerase, pcr amplification primer to and distilled water, it is characterized in that: described pcr amplification primer is to being made up of primer 1 and primer 2, wherein, the nucleotide sequence of primer 1 is as shown in SEQ ID NO:1, and the nucleotide sequence of primer 2 is as shown in SEQ ID NO:2.
4. test kit as claimed in claim 3, is characterized in that the amplification of this test kit for congenital aniridia disease Disease-causing gene, and it adopts Touch-down PCR to increase, and response procedures is:
95 DEG C of denaturations 2 minutes, then enter first circulation, 95 DEG C of sex change 40 seconds, 63 DEG C of annealing renaturation 30 seconds, 72 DEG C are extended 1min, and every circulation primary reduces by 0.5 DEG C afterwards, carry out altogether 14 circulations, enter afterwards major cycle, 95 DEG C of sex change 40 seconds, 57 DEG C of annealing renaturation 30 seconds, 72 DEG C are extended 1min, carry out altogether 25 circulations, 72 DEG C are extended 10min, 4 DEG C of preservations.
5. the application of a kind of congenital aniridia disease Disease-causing gene detection kit described in claim 3 or 4 in preparation diagnosis or detection congenital aniridia disease reagent.
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Cited By (6)
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| CN105838691A (en) * | 2016-04-18 | 2016-08-10 | 浙江大学 | Pair of transcriptional activator-like effector nucleases (TALEN) as well as encoding gene and application thereof |
| RU2654756C1 (en) * | 2017-02-16 | 2018-05-24 | Федеральное государственное автономное учреждение "Межотраслевой научно-технический комплекс "Микрохирургия глаза" имени академика С.Н. Федорова" Министерства здравоохранения Российской Федерации | Method of predicting safety of surgical treatment of patients with keratopathy associated with congenital aniridia |
| CN109735614A (en) * | 2019-02-12 | 2019-05-10 | 四川省人民医院 | A kind of congenital aniridia kit for screening |
| CN111321215A (en) * | 2020-03-11 | 2020-06-23 | 哈尔滨医科大学 | Congenital aniridia pathogenic gene mutation detection kit and application thereof |
| CN112458104A (en) * | 2020-12-04 | 2021-03-09 | 哈尔滨医科大学 | Mutant N4BP2 gene related to non-syndromic cleft lip and palate and application thereof |
| CN115612690A (en) * | 2022-12-19 | 2023-01-17 | 中国人民解放军总医院第三医学中心 | PAX6 gene mutant and application thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105838691A (en) * | 2016-04-18 | 2016-08-10 | 浙江大学 | Pair of transcriptional activator-like effector nucleases (TALEN) as well as encoding gene and application thereof |
| CN105838691B (en) * | 2016-04-18 | 2018-07-06 | 浙江大学 | A pair of of transcriptional activation increment effector nuclease and its encoding gene and application |
| RU2654756C1 (en) * | 2017-02-16 | 2018-05-24 | Федеральное государственное автономное учреждение "Межотраслевой научно-технический комплекс "Микрохирургия глаза" имени академика С.Н. Федорова" Министерства здравоохранения Российской Федерации | Method of predicting safety of surgical treatment of patients with keratopathy associated with congenital aniridia |
| CN109735614A (en) * | 2019-02-12 | 2019-05-10 | 四川省人民医院 | A kind of congenital aniridia kit for screening |
| CN109735614B (en) * | 2019-02-12 | 2022-07-22 | 四川省人民医院 | Congenital aniridia screening kit |
| CN111321215A (en) * | 2020-03-11 | 2020-06-23 | 哈尔滨医科大学 | Congenital aniridia pathogenic gene mutation detection kit and application thereof |
| CN112458104A (en) * | 2020-12-04 | 2021-03-09 | 哈尔滨医科大学 | Mutant N4BP2 gene related to non-syndromic cleft lip and palate and application thereof |
| CN115612690A (en) * | 2022-12-19 | 2023-01-17 | 中国人民解放军总医院第三医学中心 | PAX6 gene mutant and application thereof |
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