CN109385470A - One kind SNP marker relevant to non-syndromic deafness diagnosis and its application - Google Patents
One kind SNP marker relevant to non-syndromic deafness diagnosis and its application Download PDFInfo
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- CN109385470A CN109385470A CN201710678797.4A CN201710678797A CN109385470A CN 109385470 A CN109385470 A CN 109385470A CN 201710678797 A CN201710678797 A CN 201710678797A CN 109385470 A CN109385470 A CN 109385470A
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
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- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/172—Haplotypes
Abstract
The invention discloses a kind of SNP marker rs12107s relevant to non-syndromic deafness auxiliary diagnosis, and its application in the diagnostic kit of non-syndromic deafness neurological susceptibility is developed accordingly, marker of the present invention and application may make the diagnosis of non-syndromic deafness more convenient and easy, conditions of patients is quick and precisely grasped for clinician, it lays the foundation for clinical therapeutic efficacy evaluation, and provide help to be found to have the new small molecule drug targets of potential treatment value.
Description
Technical field
The invention belongs to genetic engineering and fields of biomedicine, are related to a kind of relevant to non-syndromic deafness diagnosis
SNP marker and its application.
Background technique
Harelip is a kind of abnormal by the mouth Maxillary region congenital hereditary caused by environmental factor and inherent cause collective effect
Shape.Syndrome type harelip (syndromic orofacial clefts, SOC) and non-syndrome can be divided into according to pathogenic factor
Type harelip (nonsyndromic orofacial clefts, NSOC).The former is often referred to the other structures birth defect that occurs together
Harelip, such as skin Roche syndrome (micromandibular deformity syndrome), Van der woude syndrome (underpass tunnel-cleft palate-lip
Split syndrome), palate-face-heart syndrome etc.；The latter will generally appear only as simple harelip, without the table for the other systems that occur together
Type is abnormal, can be divided into simple form harelip (cleft lip only, CLO), Cleft lip complicated cleft palate (cleft according to its clinical manifestation
Lip with cleftpalate, CLP) and simple form cleft palate (cleft palate only, CPO).Non-syndromic deafness
(NSOC) morbidity accounts for 70% or more of all harelip morbidities.
The disease incidence of NSOC is influenced by factors such as ethnic group, gender, geographical location, economic situations, average out to 1/1000-
1/500, the disease incidence highest (2.62/1000) of American Indians, followed by Japanese, Chinese, white people (1.73/
1000,1.56/1000,1.55/1000), black race's disease incidence is minimum (0.58/1000).In Chinese neonates birth defect
In epidemiology statistics, harelip is located at the third position of Newborn Birth-defects, is only second to congenital heart disease and refers to (toe) more.
The generation of harelip, it will bring neonatal feeding difficulty, linguistic function obstacle, congenital anodontia, malocclusion, jaw growth different
A series of problems, such as normal, has an adverse effect to the growth and development of infant, good appearance and physical and mental health, while also to infant
Family members cause psychology and financial burden.
NSOC is the multifactor ancestor genetic diseases of the coefficient complexity of environment and genetics factor.It is sent out in embryo growth
During educating, any influence to neuromuscular cell migrate, the cheek bow development, face dash forward fusion process in cell Proliferation, migration, differentiation and
The environment and inherent cause of intercellular signal transmitting are likely to induce the morbidity of NSOC.The harelip environmental factor being currently known
It include: tobacco, alcohol, drug, radioactive ray, maternal weight gain dysbolism, pregnant early infection and immune response etc..
In recent years, the research for NSOC inherent cause is the hot spot of harelip Study of Etiology.Have confirmed IRF6
The polymorphisms of the several genes such as (8q24), MSX1 (4p16.2), TGFα (2p13), BMP4 (14q22-q23), WNT and NSOC's
Neurological susceptibility is related.Single nucleotide polymorphism (single nucleotide polymorphisms, SNPs), which is that the mankind are heritable, to be become
Different middle one of the most common type variant form, accounts for being currently known 90% of gene pleiomorphism or more.It is primarily referred to as in genome
It is wide in human genome by the conversion of single base, dystopy, insertion or the polymorphism for lacking caused DNA sequence dna in level
General presence can occur in gene coding region, include sub-district, non-translational region, shearing site area and segment overlay region etc., and pass through shadow
Ring the transcription of gene, the spatial and temporal distributions of translation process and albumen, expression quantity and protein function etc. and disease association.
Microrna (microRNA, miRNA) is the regulation small RNA molecular of a kind of 18-25 nucleotide, belongs to non-coding
RNA family member.Research shows that miRNA wide expression in the craniofacial organization in Mouse Embryo Development period, participates in regulation face
A series of critical events of portion's embryonic development, proliferation, differentiation, apoptosis, migration and the conversion of epithelium mesenchyma including cell etc.
Process.Research find miR-96 gene SNPs can by influence miRNA oneself expression or with the binding ability of target gene, mediate
The regulation of gene participates in a variety of physiology and pathologic process.MiRNA and NSCL/P generation is closely related, and SNPs may will affect
Individual suffers from the neurological susceptibility of NSCL/P.
Summary of the invention
In view of the above technical problems, inventor has found the site rs12107 G allele and non-syndromic deafness
Correlation, and its application in the diagnostic kit of non-syndromic deafness neurological susceptibility is developed accordingly.
An object of the present invention is to propose a kind of SNP marker relevant to non-syndromic deafness auxiliary diagnosis.
The second object of the present invention is to provide the specific primer pair for detecting above-mentioned SNP marker.
The third object of the present invention is to provide above-mentioned SNP marker in preparing non-syndromic deafness diagnostic kit
Application.
The fourth object of the present invention is to provide above-mentioned specific primer to preparing non-syndromic deafness diagnostic reagent
Application in box.
The fifth object of the present invention is to provide non-syndromic deafness auxiliary diagnostic box.
Inventor, which passes through, provides the SNP of one group of high specific and sensibility highly relevant with non-syndromic deafness,
And the non-syndromic deafness auxiliary diagnostic box that can be convenient for clinical application is developed, it is the sieve of non-syndromic deafness
It looks into and diagnoses and data support is provided.
The purpose of the present invention is what is realized by following technical proposal:
A kind of SNP marker rs12107 relevant to non-syndromic deafness auxiliary diagnosis.
Provided by the present invention for diagnosing the site rs12107 of non-syndromic deafness neurological susceptibility, it is polymorphic that there are A/G
Property, when its genotype is GG, judge individual for harelip neurological susceptibility individual.
The present invention also provides the reagent for detecting SNP site genotype, the reagent be can be using this field
The reagent of any technology detection SNP known, as long as it is able to detect rs12107 loci gene type in sample.
The present invention provides a kind of methods for detecting the site rs12107, and steps are as follows for the detection method:
(1) genomic DNA is extracted；
(2) rs12107 loci gene type is detected using TaqMan detection method.
The present invention also provides the specific primers pair for detecting the SNP marker: forward primer sequence such as SEQ ID No.1
It is shown；Reverse primer sequences are as shown in SEQ ID No.2.
The present invention also provides the probes for detecting the SNP marker: probe FAM sequence is as shown in SEQ ID No.3, probe
VIC sequence is as shown in SEQ ID No.4.
The SNP marker is to preparing the application in non-syndromic deafness auxiliary diagnostic box.
The specific primer of the SNP marker is to preparing answering in non-syndromic deafness auxiliary diagnostic box
With.
The probe of the SNP marker is preparing the application in non-syndromic deafness auxiliary diagnostic box.
A kind of non-syndromic deafness auxiliary diagnostic box, the kit is for detecting in peripheral blood DNA
rs12107。
The diagnostic kit, the kit also contain the specificity amplification primer of above-mentioned SNP marker.
The diagnostic kit, the kit also contain the probe of above-mentioned SNP marker.
The diagnostic kit, which can also include that DNA extracts common agents, such as phenol, chloroform, isoamyl alcohol
Or ethyl alcohol etc..
In one embodiment of the invention, the diagnostic kit includes: to detect SNP using Taqman
Reagent needed for point gene type includes the primer for the nucleotide sequence including expanding SNP site, as shown in the table: probe
FAM is 5 '-GGCCCTGCTAGATGAGGAGT-3 ', and probe VIC is 5 '-
CTTGGGCTTCTGGAACTTGG-3 ', forward primer 5 '-
CTCTGAAGAGATTGTGGAAATGTACAA-3 ', reverse primer 5 '-
CGGTGTCTGTGATGGCATAGA-3’。
The superiority of marker of the SNP marker provided by the invention as non-syndromic deafness auxiliary diagnosis exists
In:
(1) SNP is a kind of novel gene biomarker, is different from traditional biological marker, stable, minimally invasive, be easy to examine
It surveys, the sensibility and specificity of medical diagnosis on disease will be greatly improved；
(2) SNP kit is a kind of system, comprehensive diagnostic kit, can be used for the auxiliary of non-syndromic deafness
Diagnosis facilitates the morbid state for reflecting patient, quick and precisely grasps conditions of patients for clinician, takes more individual character in time
The control prece of change provides support；
(3) development and application for passing through SNP biomarker and diagnostic kit, may make non-syndromic deafness
It diagnoses more convenient and easy, grasps conditions of patients quick and precisely for clinician, lay the foundation for clinical therapeutic efficacy evaluation, and
Help is provided to be found to have the new small molecule drug targets of potential treatment value.
Detailed description of the invention
Fig. 1 shows TaqMan Genotypings；Wherein: AA,◆GG。
Specific embodiment
The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention..Without departing substantially from spirit of that invention
In the case where essence, to modifications or substitutions made by the method for the present invention, step or condition, all belong to the scope of the present invention.
Embodiment 1
1. studying the selection (being Chinese Han nationality) of sample
Inventor has collected from Xuzhou City's First Hospital, Nanjing Children's Hospital and The Affiliated Stomatological Hospital of Nanjing Medical University
Diagnose specific non-syndromic deafness patient 1275 and normal healthy controls 1295 without harelip.All research objects are equal
It signs informed consent form (under-18s person, by its guardian's allograph), completes corresponding epidemiological survey, and provide outside 1-3mL
All blood specimens.
2. extracting genome DNA
Genomic DNA is extracted using phenol-chloroform method, genomic DNA is obtained after 75% ethanol precipitation, DNA is precipitated through TE
After dissolution measurement concentration, dilution packing -20 DEG C of refrigerators of deposit are saved backup.
Specific steps:
(1) it takes 3-5mL to freeze blood with EDTA anticoagulant storage, thaws at room temperature, it is rear that 4-5mL hemolyzing reagent is added.It moves into
8-10min is ground in 15mL dismembyator, is then moved into 15mL centrifuge tube；4,000rpm, it is centrifuged 10min；
(2) supernatant is abandoned, the hemolyzing reagent of 8-10mL is added, it is using disposable dropper that precipitating piping and druming is uniform；4,000rpm,
It is centrifuged 10min, until without obvious red；
(3) supernatant is abandoned, 1mL hemolyzing reagent is added in precipitating, is blown and beaten precipitating uniformly using micropipettor, transfer completely
Into the EP pipe of 2mL, 6,000rpm, it is centrifuged 10min；
(4) supernatant is abandoned, 1mL cell pyrolysis liquid is added, precipitating piping and druming is uniform；(released dna)
(5) add 10-20 μ l Proteinase K (20mg/mL) in every part of sample respectively, mixing 10 times, 37 DEG C of softly turning upside down
Water bath with thermostatic control is stayed overnight or 56 DEG C of water-bath 3h.(Proteinase K shifts to an earlier date 10min dissolution；It preferably turns upside down every 1h during water-bath mixed
It is even once sufficiently to react)；
(6) water-bath terminates, and in draught cupboard, 1mL (isometric) balance phenol is added in every pipe, mixing 50 times of turning upside down
Afterwards, 6,000rpm, it is centrifuged 10min.Supernatant is drawn after centrifugation to manage in another 2mL EP.(water phase contains DNA, white flock
Object is albumen)；
(7) aforesaid operations (6) are repeated；
(8) isometric chloroform/isoamyl alcohol (24:1) is added, mixing 50 times of turning upside down, 6,000rpm, it is centrifuged 10min；
(9) it draws supernatant to manage in another 1.5mL EP, 100 μ L 3M NaAc (pH=5) is added, after mixing gently, be added
The isoamyl alcohol being pre-chilled in equal volume, mixing 150 times of softly turning upside down, movement is soft when mixing, visible white after mixing
Floccule, 10,000rpm, be centrifuged 5min；(isoamyl alcohol shifts to an earlier date 1h and is put into -20 DEG C of refrigerator pre-coolings)
(10) supernatant is removed, 350-500 μ L dehydrated alcohol is added, gently vibration washing, 10,000rpm, it is centrifuged 5min, (is such as being gone
When except alcohol, DNA precipitating has suspension, can increase the revolving speed of centrifugation), alcohol is removed, EP pipe is placed on draught cupboard apoplexy
It is dry；(generally about 2h, if the time can be appropriately extended without air-drying completely)
(11) 100 μ L of TE is added and detects the concentration and purity of DNA using ultraviolet spectrometer after 4 DEG C of refrigerators save 10d,
It is dispensed according to surveyed concentration dilution, three kinds of liquid (stoste, that is, mother liquor, uses liquid at secondary mother liquor) is placed in -20 after the completion of packing
It is saved backup in DEG C refrigerator.
3. research carries out Genotyping using TaqMan method in 1275 harelip cases and 1295 controls.
Taqman allelic gene typing technology is the SNP typing method of American AB I company research and development, is more to generally acknowledge at present
One of standard of Genotyping.A pair of of both ends are added when PCR reacts for cardinal principle has the specific probe of different fluorescent markers
Identify different allele, it is FAM, VIC that 5 ' ends of probe, which are marked with reporter group, and 3 ' ends are marked with fluorescent quenching group.
When probe sequence is complete, reporter fluorescence group is quenched fluorophor and inhibits and no signal sending.With PCR into
Row, only a probe can be specifically in conjunction with corresponding template, and Taq enzyme encounters in conjunction with template during chain extension
Probe, 3 ' → 5 ' exonuclease activities will cut off probe, and reporter group cannot be inhaled far from quenching group, energy
It receives, i.e. generation fluorescence signal.It therefore can be according to the different fluorescence detected, it can be determined that the SNP allele of respective sample
Type.
3.1 reactions and quality control
3.1.1 usingUniversal PCR Master Mix(General PCR amplification premix examination
Agent) and suitable concentration primer and probe carry out PCR reaction, use ABI7900 instruments complete target fragment amplification and
Genotype detection.
3.1.2 probe and primer
Probe and primer are synthesized by Nanjing Ji Ao biotech firm.Probe FAM is 5 '-GGCCCTGCTAGATGAGGAGT-3 ',
Probe VIC is 5 '-CTTGGGCTTCTGGAACTTGG-3 ', 5 '-CTCTGAAGAGATTGTGGAAATGTACAA- of forward primer
3 ', reverse primer 5 '-CGGTGTCTGTGATGGCATAGA-3 '.
3.1.3TaqMan real-time PCR reaction system
1 TaqMan real-time PCR reaction system of table
3.1.4ABI7900PCR instrument program
Experimental arrangement: 50 DEG C, the starting preheating of 2min instrument；95 DEG C, 10min activates archaeal dna polymerase；95 DEG C, 15sec makes
DNA denaturation, 60 DEG C, 60sec makes primer and probe anneal and extend, totally 40 circulations.
After amplification cycles, fluorescence signal after amplification is read, carries out genotype interpretation, parting with 2.0 software of SDS
As a result as Fig. 1 (wherein: AA,◆ GG) and table 2 shown in.
4. result
According to testing result, case component type success rate is 97.7% (1246/1275), and control component type success rate is
97.8% (1267/1295).Frequency of genotypes AA, AG, GG genotype distribution situation are 45.0%, 44.1% and in control group sample
10.9%, the distribution situation of three kinds of genotype meets HWE (P=0.211).Frequency of genotypes AA, the distribution of AG, GG genotype in case group
Situation is 38.7%, 48.5% and 12.8%, and there are significant statistical difference (P < 0.001) for the genotype distribution with control group
(table 2).Wherein homozygous mutant GG (OR=1.36,95%CI=1.05-1.76) can dramatically increase the neurological susceptibility of NSOC.According to
The discovery of dominant inheritance model, AG/GG genotype improve NSOC neurological susceptibility (OR=1.30,95%CI=compared with AA genotype
1.10-1.52)。
We have carried out chromatographic analysis according to NSOC different clinical subtypes.Homozygous mutant GG can dramatically increase simple lip
The neurological susceptibility (OR=1.49,95%CI=1.06-2.09) split；Heterozygous mutant AG can dramatically increase harelip with the susceptible of cleft palate
Property (OR=1.43,95%CI=1.17-1.76).Dominant models analysis finds rs12107AG/GG genotype and AA genotype phase
Than improving harelip with the neurological susceptibility (OR=1.40,95%CI=1.15-1.70) of cleft palate.To confirm that site rs12107 is prominent
Become can dramatically increase Chinese han population harelip with/not with the risk of cleft palate and simple cleft palate, the detection in the site
Can be used for suffering from individual harelip with/not with the prediction of cleft palate and simple cleft palate risk.
The association study of 2 rs12107 of table and non-syndromic deafness and its hypotype
aOR, odds ratio；CI, credibility interval.
The explanation of above-described embodiment is only intended to understand method and its core concept of the invention.The scope of the present invention not by
The limitation of the specific embodiment, the embodiment are only used as illustrating the example of one aspect of the invention.This is not being departed from
, can be with several improvements and modifications are made to the present invention under the premise of inventive principle, these improvement and modification will also fall into this hair
In bright scope of protection of the claims.
Sequence table
<110>The Affiliated Stomatological Hospital of Nanjing Medical University
<120>a kind of SNP marker relevant to non-syndromic deafness diagnosis and its application
<130> 2017
<160> 4
<210> 1
<211> 27
<212> DNA
<213>artificial synthesized sequence
<400> 1
ctctgaagag attgtggaaa tgtacaa 27
<210> 2
<211> 21
<212> DNA
<213>artificial synthesized sequence
<400> 2
cggtgtctgt gatggcatag a 21
<210> 3
<211> 20
<212> DNA
<213>artificial synthesized sequence
<400> 3
ggccctgcta gatgaggagt 20
<210> 4
<211> 20
<212> DNA
<213>artificial synthesized sequence
<400> 4
cttgggcttc tggaacttgg 20
Claims (10)
1. a kind of SNP marker rs12107 relevant to non-syndromic deafness auxiliary diagnosis.
2. a kind of method of SNP marker described in detection claim 1, which is characterized in that steps are as follows:
(1) genomic DNA is extracted；
(2) rs12107 loci gene type is detected using TaqMan detection method.
3. method as claimed in claim 2, which is characterized in that the specific primer pair of detection rs12107 loci gene type are as follows: just
To primer sequence as shown in SEQ ID No.1；Reverse primer sequences are as shown in SEQ ID No.2.
4. method as claimed in claim 2, which is characterized in that the probe of detection rs12107 loci gene type are as follows: probe FAM sequence
Column are as shown in SEQ ID No.3, and probe VIC sequence is as shown in SEQ ID No.4.
5. a kind of specific primer pair of SNP marker described in detection claim 1, which is characterized in that forward primer sequence is such as
Shown in SEQ ID No.1；Reverse primer sequences are as shown in SEQ ID No.2.
6. a kind of probe of SNP marker described in detection claim 1, which is characterized in that probe FAM sequence such as SEQ ID
Shown in No.3, probe VIC sequence is as shown in SEQ ID No.4.
7. primer pair described in SNP marker, claim 5 described in claim 1 or probe as claimed in claim 6 prepare it is non-
Application in syndrome and type harelip auxiliary diagnostic box.
8. a kind of non-syndromic deafness auxiliary diagnostic box, which is characterized in that the kit is for detecting peripheral blood DNA
In rs12107.
9. kit according to any one of claims 8, which is characterized in that the kit further include primer pair described in claim 5 and/
Or probe as claimed in claim 6.
10. kit according to any one of claims 8, which is characterized in that the kit further includes that DNA extracts reagent.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106987635A (en) * | 2017-04-18 | 2017-07-28 | 南京医科大学附属口腔医院 | The susceptible SNP site of NTN1 genes and its application |
| CN107022613A (en) * | 2017-04-18 | 2017-08-08 | 南京医科大学附属口腔医院 | A kind of SNP mark related to non-syndromic deafness diagnosis and its application |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106987635A (en) * | 2017-04-18 | 2017-07-28 | 南京医科大学附属口腔医院 | The susceptible SNP site of NTN1 genes and its application |
| CN107022613A (en) * | 2017-04-18 | 2017-08-08 | 南京医科大学附属口腔医院 | A kind of SNP mark related to non-syndromic deafness diagnosis and its application |
Non-Patent Citations (1)
| Title |
|---|
| TANDI EDITH MATSHA等: "Polymorphisms in the Non-Muscle Myosin Heavy Chain Gene (MYH9) Are Associated with Lower Glomerular Filtration Rate in Mixed Ancestry Diabetic Subjects from South Africa", 《PLOS ONE》 * |
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