CN113684272A - Myocardial amyloidosis detection kit based on mutated TTR gene - Google Patents
Myocardial amyloidosis detection kit based on mutated TTR gene Download PDFInfo
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Abstract
本发明涉及人类遗传学和内科心血管技术领域，具体涉及了一种突变的TTR基因，在基因组位置chr18:29172904‑chr18:29172905处，缺失碱基G和碱基C，插入碱基A和碱基G；参考基因组版本是GRCh37。本发明还涉及一种心肌淀粉样变性检测试剂盒，包括用于扩增突变的TTR基因的引物。本发明提供的突变的TTR基因，可以作为临床辅助诊断的生物标志物；检测该变异的携带者，为受试者提供优生优育指导和遗传咨询，减少患儿出生，对心肌淀粉样变性的早期诊断，或者辅助临床判断具有重要意义。
The invention relates to the technical field of human genetics and internal medicine and cardiovascular technology, and in particular relates to a mutated TTR gene. At the genomic position chr18:29172904-chr18:29172905, base G and base C are deleted, and base A and base are inserted Base G; the reference genome version is GRCh37. The present invention also relates to a myocardial amyloidosis detection kit, comprising primers for amplifying the mutated TTR gene. The mutated TTR gene provided by the present invention can be used as a biomarker for clinical auxiliary diagnosis; the carrier of the mutation is detected, and the subjects are provided with prenatal and postnatal care guidance and genetic counseling, which can reduce the number of children born and have a positive effect on the early stage of myocardial amyloidosis. Diagnosis, or auxiliary clinical judgment is of great significance.
Description
Technical Field
The invention relates to the technical field of human genetics and internal medicine cardiovascular, in particular to a myocardial amyloidosis detection kit based on a mutated TTR gene.
Background
Amyloidosis (amyloidosis), also known as amyloidosis, myocardial amyloidosis, a disease in which amyloid protein (amyloid) deposits in the extracellular interstitial spaces of the body, thereby disrupting cellular and organ function. All tissues and organs of the whole body can be affected, but the clinical manifestations are not uniform due to different deposited amyloid and affected organs, such as liver, kidney, nerve, heart and gastrointestinal tract are common affected organs, and the affected tissues are skin, tongue and lymph node are common.
Myocardial amyloidosis is autosomal dominant inheritance, belongs to a rare disease, mostly occurs in males over 40 years old, and is few in females, wherein currently known amyloid proteins include amyloid light chain protein (AL), amyloid A protein (AA), transthyretin (TTR), beta-protein, polypeptide hormones and the like, wherein the TTR protein is encoded by a TTR gene and is mainly synthesized in the liver, and can transport thyroid hormone in plasma and cerebrospinal fluid and also can be combined with retinol binding protein to participate in the transport of retinol (vitamin A) in plasma. TTR proteins may also be involved in other intracellular processes including proteolysis, neural regeneration, autophagy, and glucose homeostasis.
Although many TTR mutation sites related to myocardial amyloidosis have been found, on the basis of previous researches, further discovery of novel TTR gene mutation sites is helpful for further research on myocardial amyloidosis, early diagnosis of myocardial amyloidosis, or assistance of clinical judgment.
Disclosure of Invention
The invention aims to provide a myocardial amyloidosis detection kit based on a mutated TTR gene aiming at myocardial amyloidosis.
The technical scheme provided by the invention is as follows:
the invention provides a mutant TTR gene, wherein at the genomic position chr18:29172904-chr18:29172905, a base G and a base C are deleted, and a base A and a base G are inserted; the reference genomic version is GRCh 37.
Preferably, the sequence of the mutated TTR gene at genomic position chr18:291728665-18:29172915 is SEQ ID NO 2.
The invention also provides a myocardial amyloidosis detection kit, which comprises a primer for amplifying the mutated TTR gene.
Preferably, the sequence of the primers is SEQ ID NO. 7 and SEQ ID NO. 8.
Thirdly, the principle and the beneficial effects of the invention are as follows:
the mutated TTR gene disclosed by the invention can be used as a biomarker for clinical auxiliary diagnosis of myocardial amyloidosis, and has important significance for early diagnosis of myocardial amyloidosis or auxiliary clinical judgment; the detection kit developed based on the mutated TTR gene can diagnose the patient carrying the mutated TTR gene, provide the bearing guidance and genetic counseling for the test subject, and reduce the birth of the sick children.
Drawings
FIG. 1 is a family diagram of example 1;
FIG. 2 is a Sanger sequencing chart of the proband in example 1;
FIG. 3 is a plot of Sanger's sequencing of non-diseased members of the pedigree of example 1.
Detailed Description
The following is further detailed by way of specific embodiments:
example 1 proband verification experiment
Sample source: in the Fuweisan Hospital of Chinese medical science, 5-10mL of whole blood samples are sent to a proband (male, 63 years old) and family members thereof on the premise of voluntarily signing an informed consent, a medical record database is established, and the data of the disease condition, family condition and the like of the proband are recorded in detail. The study was approved by the ethical committee of the unit.
Clinical profile of proband:
TABLE 1 clinical profiles of probands
Carrying out gene detection on TTR genes of proband and the family members thereof by adopting a Sanger sequencing method, and specifically comprising the following steps:
s1, extracting genome DNA;
the whole genome DNA extraction reagent of the magnetic bead method whole genome DNA extraction reagent of Jiangsu Baishinuo medical science and technology Limited company is adopted to extract the whole genome DNA of the anticoagulation sample of the human whole blood EDTA of the proband and the family members thereof, and the concentration and the purity of the DNA are detected.
S2, amplifying the TTR gene by using the designed primer combination;
upstream primer (TTR-E2F, SEQ ID NO: 7): 5'CGCTCCAGATTTCTAATACCAC 3';
downstream primer (TTR-E2R, SEQ ID NO: 8): 5'TCTGCCCCTAAATGATGCTC 3';
length: 428 bp.
As the amplification reagent, 2 XTAQA MasterMix (Dye) produced by Jiangsukang, a century Biotech Co., Ltd was used. An amplification system: 2 × Taq MasterMix (Dye)25 μ L; 1 μ L of each of the upstream and downstream primers (10 uM); DNA template<0.5 ug; by ddH2And O is supplemented to 50 mu L.
Mixing the reaction system, and carrying out amplification reaction of the target gene fragment on a PCR instrument, wherein the amplification procedure is as follows: pre-denaturation at 95 ℃ for 2 min; denaturation at 94 ℃ for 30s, annealing at 57 ℃ for 30s, and extension at 72 ℃ for 30s for 35 cycles. Final extension at 72 ℃ for 5 min.
2 mu L of PCR product is taken, 1.5% agarose gel electrophoresis is used for detecting the PCR product, and 1000bp Marker is selected as reference.
S3, PCR products were sequenced using a 3730XL Genetic Analyzer full-automatic sequencer. The reference sequences and sequencing results were obtained from the NCBI (https:// www.ncbi.nlm.nih.gov /) database and aligned.
The experimental results are as follows:
(1) in this example, it was found that proband carries mutated TTR gene, and the specific detection results are shown in Table 2 below
TABLE 2 specific detection results of mutated TTR genes
| Gene | Genomic position | Transcript number | Base change | Amino acid changes | Reference genome version |
| TTR | chr18:29172904-chr18:29172905 | NM_000371 | c.115_116delGCinsAG | p.Ala39Ser | GRCh37/hg19 |
At genomic position chr18:291728665-18:29172915, the sequence of the wild-type TTR gene is SEQ ID NO: 1: GTGAATCCAAGTGTCCTCTGATGGTCAAAGTTCTAGATGCTGTCCGAGGC，GCIs a pre-mutation base.
At genomic position chr18:291728665-18:29172915, mutationsThe sequence of TTR gene is SEQ ID NO: 2: GTGAATCCAAGTGTCCTCTGATGGTCAAAGTTCTAGATAGTGTCCGAGGC，AGIs a post-mutation base.
The reference sequence of the coding DNA of the wild-type TTR gene is SEQ ID NO: 3:
ATGGCTTCTCATCGTCTGCTCCTCCTCTGCCTTGCTGGACTGGTATTTGTGTCTGAGGCTGGCCCTACGGGCACCGGTGAATCCAAGTGTCCTCTGATGGTCAAAGTTCTAGATGCTGTCCGAGGCAGTCCTGCCATCAATGTGGCCGTGCATGTGTTCAGAAAGGCTGCTGATGACACCTGGGAGCCATTTGCCTCTGGGAAAACCAGTGAGTCTGGAGAGCTGCATGGGCTCACAACTGAGGAGGAATTTGTAGAAGGGATATACAAAGTGGAAATAGACACCAAATCTTACTGGAAGGCACTTGGCATCTCCCCATTCCATGAGCATGCAGAGGTGGTATTCACAGCCAACGACTCCGGCCCCCGCCGCTACACCATTGCCGCCCTGCTGAGCCCCTACTCCTATTCCACCACGGCTGTCGTCACCAATCCCAAGGAATG。
the sequence of the mutant TTR gene coding DNA is SEQ ID NO: 4:
ATGGCTTCTCATCGTCTGCTCCTCCTCTGCCTTGCTGGACTGGTATTTGTGTCTGAGGCTGGCCCTACGGGCACCGGTGAATCCAAGTGTCCTCTGATGGTCAAAGTTCTAGATAGTGTCCGAGGCAGTCCTGCCATCAATGTGGCCGTGCATGTGTTCAGAAAGGCTGCTGATGACACCTGGGAGCCATTTGCCTCTGGGAAAACCAGTGAGTCTGGAGAGCTGCATGGGCTCACAACTGAGGAGGAATTTGTAGAAGGGATATACAAAGTGGAAATAGACACCAAATCTTACTGGAAGGCACTTGGCATCTCCCCATTCCATGAGCATGCAGAGGTGGTATTCACAGCCAACGACTCCGGCCCCCGCCGCTACACCATTGCCGCCCTGCTGAGCCCCTACTCCTATTCCACCACGGCTGTCGTCACCAATCCCAAGGAATG。AGis the base inserted between position 115 and position 116.
c.115 — 116 delGCinsAG: the GC was deleted and AG was inserted between positions 115 and 116 as compared with the reference sequence of the encoding DNA.
The wild TTR gene coding protein is SEQ ID NO: 5:
MASHRLLLLCLAGLVFVSEAGPTGTGESKCPLMVKVLDAVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE，Ais alanine, and is a pre-mutation amino acid.
The protein coded by the mutated TTR gene is SEQ ID NO:
MASHRLLLLCLAGLVFVSEAGPTGTGESKCPLMVKVLDSVRGSPAINVAVHVFRKAADDTWEPFASGKTSESGELHGLTTEEEFVEGIYKVEIDTKSYWKALGISPFHEHAEVVFTANDSGPRRYTIAALLSPYSYSTTAVVTNPKE，Sis serine, and is a post-mutation amino acid.
p. ala39ser represents: alanine (Ala, a) at position 39 was changed to a polar uncharged serine (Ser, S).
The mutation was found to be a rare mutation by querying the population frequency database (thousand genomes: none, ESP 6500: none, ExAC: none). The amino acid changes from a nonpolar alanine (Ala, A) to a polar uncharged serine (Ser, S). The database was queried to find that the amino acid at this position was well conserved in vertebrates. The Clinvar and HGMD databases are queried to find the mutation, but different mutations p.Ala39Asp at the same site and mutations p.Leu32Pro, p.Asp38Gly, p.Asp38Asp, p.Asp38Glu, p.Val40Ile, c.142_143delgtins TCp. (Val48Ser) and the like near the site have been reported as pathogenic mutations of amyloidosis (Clinvar and HGMD databases), and the Interpro database is queried to find that the site is located in Transthyretin, thyrooxydingsite, Transthyretin/hydroxyisorate hydrosome, superfamily functional region. The literature search does not find the variation and the disease related report. According to the existing evidence: such variations are rare variations, amino acids at this position are well conserved in vertebrates, may be located in important functional domains of proteins, amino acid changes may have an effect on protein function, different variations at the same site have been reported as pathogenic variations, and are presumed to be highly suspected pathogenic mutations of myocardial amyloidosis.
(2) FIG. 1 is a family diagram of example 1; FIG. 2 is a Sanger sequencing chart of the proband in example 1; FIG. 3 is a plot of Sanger's sequencing of non-diseased members of the pedigree of example 1.
As shown in fig. 1-3, proband carries the mutated TTR gene, and both proband girls and proband children carry the mutated TTR gene. Proband carries the mutated TTR gene inherited from proband father.
Example 2 myocardial amyloidosis assay kit
This example provides a kit for detecting human TTR gene c.115 — 116delGCinsAG heterozygosis mutation, including 2 × Taq MasterMix (Dye), primers capable of detecting mutated TTR gene, etc., and the specific composition of the kit is shown in table 3 below.
The specific steps of screening the patients with c.115-116 delGCinsAG TTR gene mutation by using the kit are as follows: the DNA of the subject was extracted according to the procedure of example 1, and then the TTR gene was amplified using the designed primer combinations (SEQ ID NO:7 and SEQ ID NO:8) to obtain PCR products, and finally the PCR products were sequenced. And obtaining a reference sequence from an NCBI (https:// www.ncbi.nlm.nih.gov /) database, comparing the reference sequence with a sequencing result, judging whether the TTR gene of the testee carries the c.115-116 delGCinsAG heterozygous missense variation, and assisting the clinical confirmation of whether the testee has the patient with the c.115-116 delGCinsAG TTR gene mutation.
TABLE 3 kit composition
Example 3 mutation verification against non-familial normal persons
With reference to the method of example 1 or the myocardial amyloidosis assay kit provided in example 2, the mutant site of TTR gene c.115 — 116delGCinsAG was detected in 690 ethnic groups of unrelated normal persons (i.e., out-of-family normal persons), and none of the results detected the mutant TTR gene.
In conclusion, c.115_116delGCinsAG heterozygosis mutation based on TTR gene can cause p.Ter173Gly change of protein encoded by TTR gene, and the TTR gene is known pathogenic gene, thereby proving that the c.115_116delGCinsAG heterozygosis mutation of TTR gene is pathogenic mutation.
The foregoing detailed description of the preferred embodiments of the invention has been presented. It should be understood that numerous modifications and variations could be devised by those skilled in the art in light of the present teachings without departing from the inventive concepts. Therefore, the technical solutions available to those skilled in the art through logic analysis, reasoning and limited experiments based on the prior art according to the concept of the present invention should be within the scope of protection defined by the claims.
Sequence listing
<110> Baishinuo (Beijing) medical laboratory Co., Ltd
<120> myocardial amyloidosis detection kit based on mutated TTR gene
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cgaggcagtc ctgccatcaa tgtggccgtg catgtgttca gaaaggctgc tgatgacacc 180
tgggagccat ttgcctctgg gaaaaccagt gagtctggag agctgcatgg gctcacaact 240
gaggaggaat ttgtagaagg gatatacaaa gtggaaatag acaccaaatc ttactggaag 300
gcacttggca tctccccatt ccatgagcat gcagaggtgg tattcacagc caacgactcc 360
ggcccccgcc gctacaccat tgccgccctg ctgagcccct actcctattc caccacggct 420
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cgaggcagtc ctgccatcaa tgtggccgtg catgtgttca gaaaggctgc tgatgacacc 180
tgggagccat ttgcctctgg gaaaaccagt gagtctggag agctgcatgg gctcacaact 240
gaggaggaat ttgtagaagg gatatacaaa gtggaaatag acaccaaatc ttactggaag 300
gcacttggca tctccccatt ccatgagcat gcagaggtgg tattcacagc caacgactcc 360
ggcccccgcc gctacaccat tgccgccctg ctgagcccct actcctattc caccacggct 420
gtcgtcacca atcccaagga atg 443
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Met Ala Ser His Arg Leu Leu Leu Leu Cys Leu Ala Gly Leu Val Phe
1 5 10 15
Val Ser Glu Ala Gly Pro Thr Gly Thr Gly Glu Ser Lys Cys Pro Leu
20 25 30
Met Val Lys Val Leu Asp Ala Val Arg Gly Ser Pro Ala Ile Asn Val
35 40 45
Ala Val His Val Phe Arg Lys Ala Ala Asp Asp Thr Trp Glu Pro Phe
50 55 60
Ala Ser Gly Lys Thr Ser Glu Ser Gly Glu Leu His Gly Leu Thr Thr
65 70 75 80
Glu Glu Glu Phe Val Glu Gly Ile Tyr Lys Val Glu Ile Asp Thr Lys
85 90 95
Ser Tyr Trp Lys Ala Leu Gly Ile Ser Pro Phe His Glu His Ala Glu
100 105 110
Val Val Phe Thr Ala Asn Asp Ser Gly Pro Arg Arg Tyr Thr Ile Ala
115 120 125
Ala Leu Leu Ser Pro Tyr Ser Tyr Ser Thr Thr Ala Val Val Thr Asn
130 135 140
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145
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Met Ala Ser His Arg Leu Leu Leu Leu Cys Leu Ala Gly Leu Val Phe
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Met Val Lys Val Leu Asp Ser Val Arg Gly Ser Pro Ala Ile Asn Val
35 40 45
Ala Val His Val Phe Arg Lys Ala Ala Asp Asp Thr Trp Glu Pro Phe
50 55 60
Ala Ser Gly Lys Thr Ser Glu Ser Gly Glu Leu His Gly Leu Thr Thr
65 70 75 80
Glu Glu Glu Phe Val Glu Gly Ile Tyr Lys Val Glu Ile Asp Thr Lys
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Ser Tyr Trp Lys Ala Leu Gly Ile Ser Pro Phe His Glu His Ala Glu
100 105 110
Val Val Phe Thr Ala Asn Asp Ser Gly Pro Arg Arg Tyr Thr Ile Ala
115 120 125
Ala Leu Leu Ser Pro Tyr Ser Tyr Ser Thr Thr Ala Val Val Thr Asn
130 135 140
Pro Lys Glu
145
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cgctccagat ttctaatacc ac 22
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tctgccccta aatgatgctc 20
Claims (4)
1. A mutated TTR gene, characterized in that at genomic position chr18:29172904-chr18:29172905, base G and base C are deleted, and base A and base G are inserted; the reference genomic version is GRCh 37.
2. The mutated TTR gene according to claim 1, having the sequence SEQ ID NO 2 at genomic position chr18:291728665-18: 29172915.
3. A myocardial amyloidosis assay kit, characterized in that it comprises primers for amplifying the mutated TTR gene according to claim 1 or 2.
4. The myocardial amyloidosis assay kit according to claim 3, characterized in that the sequences of the primers are SEQ ID NO 7 and SEQ ID NO 8.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105659093A (en) * | 2013-06-28 | 2016-06-08 | 株式会社Ｍｃｂｉ | Biomarkers for cognitive dysfunction diseases and method for detecting cognitive dysfunction disease using biomarkers |
| CN111163633A (en) * | 2017-09-29 | 2020-05-15 | 瑞泽恩制药公司 | Non-human animals comprising a humanized TTR locus and methods of using the same |
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2021
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105659093A (en) * | 2013-06-28 | 2016-06-08 | 株式会社Ｍｃｂｉ | Biomarkers for cognitive dysfunction diseases and method for detecting cognitive dysfunction disease using biomarkers |
| CN111163633A (en) * | 2017-09-29 | 2020-05-15 | 瑞泽恩制药公司 | Non-human animals comprising a humanized TTR locus and methods of using the same |
Non-Patent Citations (6)
| Title |
|---|
| M J SARAIVA: "Transthyretin mutations in health and disease", HUM MUTAT., vol. 5, no. 3, pages 191 - 196 * |
| M J SARAIVA: "Transthyretin mutations in hyperthyroxinemia and amyloid diseases", HUM MUTAT., vol. 17, no. 6, pages 493 - 503 * |
| 佚名: "AH002923.2", NCBI, pages 1 - 3 * |
| 佚名: "NM_000371.4(TTR):c.116C>A (p.Ala39Asp)", Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/clinvar/variation/565560/> * |
| 朱培冉;吴秋月;余毛毛;张明超;倪梦霞;刘帅妹;蒋卫军;张静;李卫巍;曹进;李伊;薛春燕;夏欣一;: "一汉族玻璃体淀粉样变性家系的TTR基因突变检测", 临床检验杂志, no. 03 * |
| 李广镰等主编: "心血管遗传病学", vol. 7, 31 December 1994, 北京医科大学；中国协和医科大学联合出版社, pages: 268 - 269 * |
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