20 results on '"Yi, Qing"'
Search Results
2. SMAD4 loss-of-function mutation predisposes to congenital heart disease
- Author
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Wang, Yin, Xu, Ying-Jia, Yang, Chen-Xi, Huang, Ri-Tai, Xue, Song, Yuan, Fang, and Yang, Yi-Qing
- Published
- 2023
- Full Text
- View/download PDF
3. SOX17 loss-of-function variation underlying familial congenital heart disease
- Author
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Zhao, Lan, Jiang, Wei-Feng, Yang, Chen-Xi, Qiao, Qi, Xu, Ying-Jia, Shi, Hong-Yu, Qiu, Xing-Biao, Wu, Shao-Hui, and Yang, Yi-Qing
- Published
- 2021
- Full Text
- View/download PDF
4. ISL1 loss-of-function variation causes familial atrial fibrillation
- Author
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Wu, Shao-Hui, Wang, Xin-Hua, Xu, Ying-Jia, Gu, Jia-Ning, Yang, Chen-Xi, Qiao, Qi, Guo, Xiao-Juan, Guo, Yu-Han, Qiu, Xing-Biao, Jiang, Wei-Feng, and Yang, Yi-Qing
- Published
- 2020
- Full Text
- View/download PDF
5. Identification and functional characterization of KLF5 as a novel disease gene responsible for familial dilated cardiomyopathy
- Author
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Di, Ruo-Min, Yang, Chen-Xi, Zhao, Cui-Mei, Yuan, Fang, Qiao, Qi, Gu, Jia-Ning, Li, Xiu-Mei, Xu, Ying-Jia, and Yang, Yi-Qing
- Published
- 2020
- Full Text
- View/download PDF
6. HAND2 loss-of-function mutation causes familial dilated cardiomyopathy
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Liu, Hua, Xu, Ying-Jia, Li, Ruo-Gu, Wang, Zhang-Sheng, Zhang, Min, Qu, Xin-Kai, Qiao, Qi, Li, Xiu-Mei, Di, Ruo-Min, Qiu, Xing-Biao, and Yang, Yi-Qing
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- 2019
- Full Text
- View/download PDF
7. A novel NR2F2 loss-of-function mutation predisposes to congenital heart defect
- Author
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Qiao, Xiao-Hui, Wang, Qian, Wang, Juan, Liu, Xing-Yuan, Xu, Ying-Jia, Huang, Ri-Tai, Xue, Song, Li, Yan-Jie, Zhang, Min, Qu, Xin-Kai, Li, Ruo-Gu, Qiu, Xing-Biao, and Yang, Yi-Qing
- Published
- 2018
- Full Text
- View/download PDF
8. VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy
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Hong-Yu Shi, Meng-Shi Xie, Yu-Han Guo, Chen-Xi Yang, Jia-Ning Gu, Qi Qiao, Ruo-Min Di, Xing-Biao Qiu, Ying-Jia Xu, and Yi-Qing Yang
- Subjects
Genetics ,General Medicine ,Genetics (clinical) - Published
- 2023
9. GATA6 loss-of-function mutation in atrial fibrillation
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Yang, Yi-Qing, Li, Li, Wang, Juan, Zhang, Xian-Ling, Li, Ruo-Gu, Xu, Ying-Jia, Tan, Hong-Wei, Wang, Xin-Hua, Jiang, Jin-Qi, Fang, Wei-Yi, and Liu, Xu
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- 2012
- Full Text
- View/download PDF
10. SMAD4 loss-of-function mutation predisposes to congenital heart disease
- Author
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Yin Wang, Ying-Jia Xu, Chen-Xi Yang, Ri-Tai Huang, Song Xue, Fang Yuan, and Yi-Qing Yang
- Subjects
Genetics ,General Medicine ,Genetics (clinical) - Abstract
Congenital heart disease (CHD) represents the most frequent developmental deformity in human beings and accounts for substantial morbidity and mortality worldwide. Accumulating investigations underscore the strong inherited basis of CHD, and pathogenic variations in100 genes have been related to CHD. Nevertheless, the heritable defects underpinning CHD remain elusive in most cases, mainly because of the pronounced genetic heterogeneity. In this investigation, a four-generation family with CHD was recruited and clinically investigated. Via whole-exome sequencing and Sanger sequencing assays in selected family members, a heterozygous variation in the SMAD4 gene (coding for a transcription factor essential for cardiovascular morphogenesis), NM_005359.6: c.285T A; p.(Tyr95*), was identified to be in co-segregation with autosomal-dominant CHD in the entire family. The truncating variation was not observed in 460 unrelated non-CHD volunteers employed as control subjects. Functional exploration by dual-reporter gene analysis demonstrated that Tyr95*-mutant SMAD4 lost transactivation of its two key downstream target genes NKX2.5 and ID2, which were both implicated with CHD. Additionally, the variation nullified the synergistic transcriptional activation between SMAD4 and GATA4, another transcription factor involved in CHD. These data strongly indicate SMAD4 may be associated with CHD and shed more light on the molecular pathogenesis underlying CHD, implying potential implications for antenatal precise prevention and prognostic risk stratification of the patients affected with CHD.
- Published
- 2023
11. SOX17 loss-of-function variation underlying familial congenital heart disease
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Chen-Xi Yang, Yi-Qing Yang, Xing-Biao Qiu, Hong-Yu Shi, Lan Zhao, Weifeng Jiang, Qi Qiao, Ying-Jia Xu, and Shaohui Wu
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0301 basic medicine ,Adult ,Heart Defects, Congenital ,Male ,medicine.medical_specialty ,dbSNP ,Adolescent ,Penetrance ,030105 genetics & heredity ,medicine.disease_cause ,03 medical and health sciences ,symbols.namesake ,Loss of Function Mutation ,Molecular genetics ,Chlorocebus aethiops ,Genetics ,medicine ,SOXF Transcription Factors ,Animals ,Humans ,cardiovascular diseases ,Child ,Exome ,Genetics (clinical) ,Loss function ,Sanger sequencing ,Mutation ,business.industry ,Genetic heterogeneity ,General Medicine ,Middle Aged ,Pedigree ,030104 developmental biology ,Codon, Nonsense ,COS Cells ,symbols ,Female ,business ,HeLa Cells - Abstract
As the most prevalent form of human birth defect, congenital heart disease (CHD) contributes to substantial morbidity, mortality and socioeconomic burden worldwide. Aggregating evidence has convincingly demonstrated that genetic defects exert a pivotal role in the pathogenesis of CHD, and causative mutations in multiple genes have been causally linked to CHD. Nevertheless, CHD is of pronounced genetic heterogeneity, and the genetic components underpinning CHD in the overwhelming majority of patients remain obscure. In this research, a four-generation consanguineous family suffering from CHD transmitted in an autosomal dominant mode was recruited. By whole-exome sequencing and bioinformatics analyses as well as Sanger sequencing analyses of the family members, a new heterozygous SOX17 variation, NM_022454.4: c.553G > T; p.(Glu185*), was identified to co-segregate with CHD in the family, with complete penetrance. The nonsense variation was neither detected in 310 unrelated healthy volunteers used as controls nor retrieved in such population genetics databases as the Exome Aggregation Consortium database, Genome Aggregation Database, and the Single Nucleotide Polymorphism database. Functional assays by utilizing a dual-luciferase reporter assay system unveiled that the Glu185*-mutant SOX17 protein had no transcriptional activity on its two target genes NOTCH1 and GATA4, which have been reported to cause CHD. Furthermore, the mutation abrogated the synergistic transactivation between SOX17 and NKX2.5, another established CHD-causing transcription factor. These findings firstly indicate SOX17 loss-of-function mutation predisposes to familial CHD, which adds novel insight to the molecular mechanism of CHD, implying potential implications for genetic risk appraisal and individualized prophylaxis of the family members affected with CHD.
- Published
- 2020
12. A novel NR2F2 loss-of-function mutation predisposes to congenital heart defect
- Author
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Yi-Qing Yang, Juan Wang, Ruo-Gu Li, Song Xue, Xing-Biao Qiu, Ri-Tai Huang, Xing-Yuan Liu, Xiao-Hui Qiao, Ying-Jia Xu, Yan-Jie Li, Qian Wang, Min Zhang, and Xin-Kai Qu
- Subjects
Adult ,Heart Septal Defects, Ventricular ,Male ,0301 basic medicine ,Adolescent ,Genetic counseling ,Nonsense mutation ,Penetrance ,030204 cardiovascular system & hematology ,COUP Transcription Factor II ,03 medical and health sciences ,0302 clinical medicine ,Mutation Carrier ,Loss of Function Mutation ,Double outlet right ventricle ,Chlorocebus aethiops ,Genetics ,Animals ,Humans ,Medicine ,Genetic Predisposition to Disease ,cardiovascular diseases ,Child ,Genetics (clinical) ,business.industry ,Genetic heterogeneity ,Infant ,Autosomal dominant trait ,General Medicine ,Middle Aged ,medicine.disease ,Double Outlet Right Ventricle ,HEK293 Cells ,030104 developmental biology ,Child, Preschool ,COS Cells ,Mutation (genetic algorithm) ,Female ,business - Abstract
Congenital heart defect (CHD) is the most common type of birth defect in humans and a leading cause of infant morbidity and mortality. Previous studies have demonstrated that genetic defects play a pivotal role in the pathogenesis of CHD. However, the genetic basis of CHD remains poorly understood due to substantial genetic heterogeneity. In this study, the coding exons and splicing boundaries of the NR2F2 gene, which encodes a pleiotropic transcription factor required for normal cardiovascular development, were sequenced in 168 unrelated patients with CHD, and a novel mutation (c.247G > T, equivalent to p.G83X) was detected in a patient with double outlet right ventricle as well as ventricular septal defect. Genetic scanning of the mutation carrier's relatives available showed that the mutation was present in all affected family members but absent in unaffected family members. Analysis of the index patient's pedigree displayed that the mutation co-segregated with CHD, which was transmitted as an autosomal dominant trait with complete penetrance. The nonsense mutation was absent in 230 unrelated, ethnically-matched healthy individuals used as controls. Functional deciphers by using a dual-luciferase reporter assay system revealed that the mutant NR2F2 protein had no transcriptional activity as compared with its wild-type counterpart. Furthermore, the mutation abrogated the synergistic transcriptional activation between NR2F2 and GATA4, another core cardiac transcription factor associated with CHD. This study firstly associates NR2F2 loss-of-function mutation with an increased susceptibility to double outlet right ventricle in humans, which provides further significant insight into the molecular mechanisms underpinning CHD, suggesting potential implications for genetic counseling of CHD families and personalized treatment of CHD patients.
- Published
- 2018
13. Identification and functional characterization of KLF5 as a novel disease gene responsible for familial dilated cardiomyopathy
- Author
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Chen-Xi Yang, Xiu-Mei Li, Yi-Qing Yang, Jia-Ning Gu, Ruo-Min Di, Fang Yuan, Cui-Mei Zhao, Qi Qiao, and Ying-Jia Xu
- Subjects
0301 basic medicine ,Proband ,Adult ,Cardiomyopathy, Dilated ,Male ,Nonsense mutation ,Kruppel-Like Transcription Factors ,030105 genetics & heredity ,Biology ,medicine.disease_cause ,03 medical and health sciences ,Exon ,Asian People ,Chlorocebus aethiops ,Genetics ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,cardiovascular diseases ,Gene ,Genetics (clinical) ,Mutation ,Genetic heterogeneity ,General Medicine ,Middle Aged ,Penetrance ,Transplantation ,030104 developmental biology ,COS Cells ,cardiovascular system ,Female ,HeLa Cells - Abstract
As a prevalent primary myocardial disease, dilated cardiomyopathy (DCM) represents the most common cause of heart failure in the young and the most frequent indication for cardiac transplantation. Aggregating evidence highlights the genetic basis of DCM. However, due to substantial genetic heterogeneity, the genetic defects of DCM in most cases remain elusive. In the current investigation, the entire coding exons and splicing junctions of the KLF5 gene, which encodes a key transcription factor required for cardiac structural and functional remodeling, were sequenced in 234 probands affected with DCM, and a heterozygous KLF5 mutation, NM_001730.5: c.1100T > A; p.(Leu367*), was identified in a proband. Genetic analysis of the proband's family members revealed that the identified KLF5 mutation co-segregated with DCM in the family with complete penetrance. The nonsense mutation was neither detected in 506 control individuals nor reported in such population-genetics databases as ExAC, dbSNP and gnomAD. Biological assays with a dual-luciferase reporter assay system demonstrated that the mutant KLF5 protein had no transcriptional activity when compared with its wild-type counterpart. Furthermore, the mutation abrogated the synergistic transactivation between KLF5 and NFKB1, another pivotal transcription factor that has been causally linked to DCM. The whole-exome sequencing analysis of the proband's family members revealed no other causative genes. The findings indicate KLF5 as a new gene contributing to DCM in humans, implying potential implications for the precision medicine of DCM.
- Published
- 2019
14. ISL1 loss-of-function variation causes familial atrial fibrillation
- Author
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Chen-Xi Yang, Shaohui Wu, Xing-Hua Wang, Jia-Ning Gu, Ying-Jia Xu, Weifeng Jiang, Xiao-Juan Guo, Qi Qiao, Yu-Han Guo, Xing-Biao Qiu, and Yi-Qing Yang
- Subjects
Adult ,Male ,0301 basic medicine ,LIM-Homeodomain Proteins ,Population ,030105 genetics & heredity ,Biology ,03 medical and health sciences ,Loss of Function Mutation ,Atrial Fibrillation ,Genetics ,medicine ,Humans ,MEF2C ,education ,Genetics (clinical) ,Loss function ,Exome sequencing ,Aged ,Genetic testing ,education.field_of_study ,medicine.diagnostic_test ,MEF2 Transcription Factors ,GATA4 ,General Medicine ,Middle Aged ,medicine.disease ,Penetrance ,GATA4 Transcription Factor ,Pedigree ,HEK293 Cells ,030104 developmental biology ,Codon, Nonsense ,Homeobox Protein Nkx-2.5 ,Female ,T-Box Domain Proteins ,Familial atrial fibrillation ,Transcription Factors - Abstract
Atrial fibrillation (AF) represents the most frequent form of sustained cardiac rhythm disturbance, affecting approximately 1% of the general population worldwide, and confers a substantially enhanced risk of cerebral stroke, heart failure, and death. Increasing epidemiological studies have clearly demonstrated a strong genetic basis for AF, and variants in a wide range of genes, including those coding for ion channels, gap junction channels, cardiac structural proteins and transcription factors, have been identified to underlie AF. Nevertheless, the genetic pathogenesis of AF is complex and still far from completely understood. Here, whole-exome sequencing and bioinformatics analyses of a three-generation family with AF were performed, and after filtering variants by multiple metrics, we identified a heterozygous variant in the ISL1 gene (encoding a transcription factor critical for embryonic cardiogenesis and postnatal cardiac remodeling), NM_002202.2: c.481G > T; p.(Glu161*), which was validated by Sanger sequencing and segregated with autosome-dominant AF in the family with complete penetrance. The nonsense variant was absent from 284 unrelated healthy individuals used as controls. Functional assays with a dual-luciferase reporter assay system revealed that the truncating ISL1 protein lost transcriptional activation on the verified target genes MEF2C and NKX2-5. Additionally, the variant nullified the synergistic transactivation between ISL1 and TBX5 as well as GATA4, two other transcription factors that have been implicated in AF. The findings suggest ISL1 as a novel gene contributing to AF, which adds new insight to the genetic mechanisms underpinning AF, implying potential implications for genetic testing and risk stratification of the AF family members.
- Published
- 2020
15. HAND2 loss-of-function mutation causes familial dilated cardiomyopathy
- Author
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Hua Liu, Xiu-Mei Li, Xin-Kai Qu, Min Zhang, Yi-Qing Yang, Ruo-Min Di, Ying-Jia Xu, Zhang-Sheng Wang, Qi Qiao, Xing-Biao Qiu, and Ruo-Gu Li
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0301 basic medicine ,Adult ,Cardiomyopathy, Dilated ,Male ,Heterozygote ,animal structures ,Mutant ,Nonsense mutation ,Cardiomyopathy ,Penetrance ,030105 genetics & heredity ,Biology ,medicine.disease_cause ,03 medical and health sciences ,Mutation Carrier ,Loss of Function Mutation ,Genetics ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Humans ,cardiovascular diseases ,Genetics (clinical) ,Mutation ,GATA4 ,Dilated cardiomyopathy ,General Medicine ,Middle Aged ,musculoskeletal system ,medicine.disease ,030104 developmental biology ,HEK293 Cells ,embryonic structures ,cardiovascular system ,Female ,HeLa Cells - Abstract
As two members of the basic helix-loop-helix family of transcription factors, HAND1 and HAND2 are both required for the embryonic cardiogenesis and postnatal ventricular structural remodeling. Recently a HAND1 mutation has been reported to cause dilated cardiomyopathy (DCM). However, the association of a HAND2 mutation with DCM is still to be ascertained. In this research, the coding regions and splicing junction sites of the HAND2 gene were sequenced in 206 unrelated patients affected with idiopathic DCM, and a new heterozygous HAND2 mutation, NM_021973.2: c.199G > T; p.(Glu67*), was discovered in an index patient with DCM. The nonsense mutation was absent in 300 unrelated, ethnically-matched healthy persons. Genetic scan of the mutation carrier's family members revealed that the genetic mutation co-segregated with DCM, which was transmitted in an autosomal dominant fashion, with complete penetrance. Functional deciphers unveiled that the mutant HAND2 protein had no transcriptional activity. In addition, the mutation abrogated the synergistic transcriptional activation between HAND2 and GATA4 or between HAND2 and NKX2.5, two other cardiac transcription factors that have been implicated in DCM. These research findings firstly suggest HAND2 as a novel gene predisposing to DCM in humans, which adds novel insight to the molecular pathogenesis of DCM, implying potential implications in the design of personized preventive and therapeutic strategies against DCM.
- Published
- 2018
16. Prevalence and spectrum of Nkx2.6 mutations in patients with congenital heart disease
- Author
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Ruo-Gu Li, Wei-Yi Fang, Lan Zhao, Xin-Kai Qu, Fang Yuan, Shi-Hong Ni, Yi-Qing Yang, Xing-Biao Qiu, Lei Xu, Xin-Li, Ying-Jia Xu, Dong Wei, and Xing-Yuan Liu
- Subjects
Heart Defects, Congenital ,Heart Septal Defects, Ventricular ,Male ,Heart disease ,Disease ,Biology ,medicine.disease_cause ,Pathogenesis ,Exon ,Asian People ,stomatognathic system ,Genetics ,medicine ,Humans ,cardiovascular diseases ,Gene ,Genetics (clinical) ,Tetralogy of Fallot ,Homeodomain Proteins ,Mutation ,Genetic heterogeneity ,General Medicine ,respiratory system ,medicine.disease ,Double Outlet Right Ventricle ,embryonic structures ,Homeobox Protein Nkx-2.5 ,cardiovascular system ,Female ,Transcription Factors - Abstract
Congenital heart disease (CHD) is the most common form of birth defect and is the most prevalent non-infectious cause of infant death. A growing body of evidence documents that genetic defects are involved in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disease and the genetic basis underpinning CHD in an overwhelming majority of patients remain unclear. In this study, the coding exons and flanking introns of the Nkx2.6 gene, which codes for a homeodomain-containing transcription factor important for normal cardiovascular development, were sequenced in 320 unrelated patients with CHD, and two novel heterozygous Nkx2.6 mutations, p.V176M and p.K177X, were identified in two unrelated patients with CHD, respectively, including a patient with tetralogy of Fallot and a patient with double outlet of right ventricle and ventricular septal defect. The mutations were absent in 400 control chromosomes and the altered amino acids were completely conserved evolutionarily across species. Due to unknown transcriptional targets of Nkx2.6, the functional consequences of the identified mutations at transcriptional activity were evaluated by using Nkx2.5 as a surrogate. Alignment between human Nkx2.6 and Nkx2.5 proteins showed that V176M-mutant Nkx2.6 was equivalent to V182M-mutant Nkx2.5 and K177X-mutant Nkx2.6 was equal to K183X-mutant Nkx2.5, and introduction of V182M or K183X into Nkx2.5 significantly diminished its transcriptional activating function when compared with its wild-type counterpart. To our knowledge, this is the first report on the association of Nkx2.6 loss-of-function mutation with increased susceptibility to tetralogy of Fallot or double outlet of right ventricle and ventricular septal defect, providing novel insight into the molecular mechanism of CHD.
- Published
- 2014
17. GATA6 loss-of-function mutation in atrial fibrillation
- Author
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Li Li, Xian-Ling Zhang, Ruo-Gu Li, Yi-Qing Yang, Hong-Wei Tan, Jin-Qi Jiang, Juan Wang, Wei-Yi Fang, Xin-Hua Wang, Xu Liu, and Ying-Jia Xu
- Subjects
Adult ,Male ,Heterozygote ,Transcription, Genetic ,Mutation, Missense ,Penetrance ,Biology ,medicine.disease_cause ,Bioinformatics ,Mutation Carrier ,GATA6 Transcription Factor ,Atrial Fibrillation ,Genetics ,medicine ,Humans ,Genetics (clinical) ,Genes, Dominant ,Mutation ,GATA6 ,Genetic heterogeneity ,Autosomal dominant trait ,Cardiac arrhythmia ,Heterozygote advantage ,General Medicine ,Middle Aged ,Pedigree ,Female - Abstract
Atrial fibrillation (AF) is the most common type of sustained cardiac arrhythmia and is associated with substantial morbidity and mortality. Increasing evidence demonstrates that hereditary defects are involved in the pathogenesis of AF. However, AF is of remarkable genetic heterogeneity, and the heritable components responsible for AF in the majority of patients remain unclear. In this study, the entire coding region of the GATA6 gene, which encodes a zinc-finger transcription factor crucial for cardiogenesis, was sequenced in 138 unrelated patients with lone AF, and a novel heterozygous GATA6 mutation, c.704A > C equivalent to p.Y235S, was identified in a patient. The detected substitution, which altered the amino acid highly conserved evolutionarily across species, was absent in 200 unrelated ethnically matched healthy individuals, and was predicted to be disease-causing by MutationTaster. Genetic analysis of the available relatives of the mutation carrier showed that in the family the variation co-segregated with the disease transmitted as an autosomal dominant trait, with complete penetrance. The functional analysis performed using a luciferase reporter assay system revealed that the mutant GATA6 protein resulted in significantly decreased transcriptional activity compared with its wild-type counterpart. These findings provide novel insight into the molecular pathophysiology implicated in AF, suggesting the potential implications in the prophylactic strategy and effective therapy for this common arrhythmia.
- Published
- 2012
18. Prevalence and spectrum of Nkx2.6 mutations in patients with congenital heart disease
- Author
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Zhao, Lan, Ni, Shi-Hong, Liu, Xing-Yuan, Wei, Dong, Yuan, Fang, Xu, Lei, Xin-Li, Li, Ruo-Gu, Qu, Xin-Kai, Xu, Ying-Jia, Fang, Wei-Yi, Yang, Yi-Qing, and Qiu, Xing-Biao
- Published
- 2014
- Full Text
- View/download PDF
19. A novel PITX2c loss-of-function mutation associated with familial atrial fibrillation
- Author
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Wang, Jun, Zhang, Dai-Fu, Sun, Yu-Min, and Yang, Yi-Qing
- Published
- 2014
- Full Text
- View/download PDF
20. A novel PITX2c loss-of-function mutation associated with familial atrial fibrillation
- Author
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Yu-Min Sun, Dai-Fu Zhang, Yi-Qing Yang, and Jun Wang
- Subjects
Adult ,Male ,Mutant ,DNA Mutational Analysis ,Molecular Sequence Data ,Mutation, Missense ,Biology ,medicine.disease_cause ,Bioinformatics ,Pathogenesis ,Atrial Fibrillation ,Genetics ,medicine ,Missense mutation ,Humans ,Genetic Predisposition to Disease ,Amino Acid Sequence ,Gene ,Genetics (clinical) ,Genetic Association Studies ,Homeodomain Proteins ,Mutation ,Base Sequence ,Genetic heterogeneity ,General Medicine ,Middle Aged ,medicine.disease ,Penetrance ,Pedigree ,Case-Control Studies ,Female ,Familial atrial fibrillation ,Transcription Factors - Abstract
Atrial fibrillation (AF) represents the most prevalent form of sustained cardiac arrhythmia and contributes substantially to cardiovascular morbidity and mortality. Aggregating evidence demonstrates that genetic risk factors play an important role in the pathogenesis of AF. However, AF is a genetically heterogeneous disease and the genetic defects responsible for AF in an overwhelming majority of patients remain unclear. In the present study, the whole coding region and splice junction sites of the PITX2c gene, which encodes a paired-like homeobox transcription factor essential for normal cardiovascular development, were sequenced in 160 unrelated patients with lone AF, and a novel heterozygous mutation, c.349C > T equivalent to p.P117S, was identified in a patient with positive family history of AF. The missense mutation, which co-segregated with AF in the family with complete penetrance and was absent in 700 unrelated ethnically matched healthy individuals, altered the amino acid completely conserved evolutionarily across species and was predicted to be pathogenic by MutationTaster and PolyPhen-2. Biological assays revealed that the mutant PITX2c protein was associated with significantly decreased transcriptional activity when compared with its wild-type counterpart. The findings implicate PITX2c loss-of-function mutation in familial AF for the first time, providing novel insight into the molecular pathology of AF.
- Published
- 2013
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