23 results on '"Ying Jia"'
Search Results
2. ZBTB17 loss-of-function mutation contributes to familial dilated cardiomyopathy
- Author
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Sun, Yu-Min, Wang, Jun, Xu, Ying-Jia, Wang, Xin-Hua, Yuan, Fang, Liu, Hua, Li, Ruo-Gu, Zhang, Min, Li, Yan-Jie, Shi, Hong-Yu, Zhao, Liang, Qiu, Xing-Biao, Qu, Xin-Kai, and Yang, Yi-Qing
- Published
- 2018
- Full Text
- View/download PDF
3. Identification of BMP10 as a Novel Gene Contributing to Dilated Cardiomyopathy
- Author
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Jia-Ning Gu, Chen-Xi Yang, Yuan-Yuan Ding, Qi Qiao, Ruo-Min Di, Yu-Min Sun, Jun Wang, Ling Yang, Ying-Jia Xu, and Yi-Qing Yang
- Subjects
Clinical Biochemistry ,dilated cardiomyopathy ,molecular genetics ,transcriptional regulation ,BMP10 ,reporter gene analysis - Abstract
Dilated cardiomyopathy (DCM), characterized by left ventricular or biventricular enlargement with systolic dysfunction, is the most common type of cardiac muscle disease. It is a major cause of congestive heart failure and the most frequent indication for heart transplantation. Aggregating evidence has convincingly demonstrated that DCM has an underlying genetic basis, though the genetic defects responsible for DCM in a larger proportion of cases remain elusive, motivating the ongoing research for new DCM-causative genes. In the current investigation, a multigenerational family affected with autosomal-dominant DCM was recruited from the Chinese Han population. By whole-exome sequencing and Sanger sequencing analyses of the DNAs from the family members, a new BMP10 variation, NM_014482.3:c.166C > T;p.(Gln56*), was discovered and verified to be in co-segregation with the DCM phenotype in the entire family. The heterozygous BMP10 variant was not detected in 268 healthy volunteers enrolled as control subjects. The functional measurement via dual-luciferase reporter assay revealed that Gln56*-mutant BMP10 lost the ability to transactivate its target genes NKX2.5 and TBX20, two genes that had been causally linked to DCM. The findings strongly indicate BMP10 as a new gene contributing to DCM in humans and support BMP10 haploinsufficiency as an alternative pathogenic mechanism underpinning DCM, implying potential implications for the early genetic diagnosis and precision prophylaxis of DCM.
- Published
- 2023
- Full Text
- View/download PDF
4. Detection and functional characterization of a novel MEF2A variation responsible for familial dilated cardiomyopathy
- Author
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Chen-Xi Yang, Min Zhang, Ruo-Gu Li, Cui-Mei Zhao, Ying-Jia Xu, Jia-Ning Gu, Xing-Biao Qiu, Qi Qiao, Yi-Qing Yang, and Yu-Han Guo
- Subjects
0301 basic medicine ,Genetics ,Sanger sequencing ,medicine.diagnostic_test ,Genetic heterogeneity ,Biochemistry (medical) ,Clinical Biochemistry ,Cardiomyopathy ,Dilated cardiomyopathy ,General Medicine ,030204 cardiovascular system & hematology ,Biology ,medicine.disease ,Penetrance ,03 medical and health sciences ,symbols.namesake ,030104 developmental biology ,0302 clinical medicine ,Genetic variation ,cardiovascular system ,medicine ,symbols ,cardiovascular diseases ,MYH6 ,Genetic testing - Abstract
Objectives Dilated cardiomyopathy (DCM) represents the most frequent form of cardiomyopathy, leading to heart failure, cardiac arrhythmias and death. Accumulating evidence convincingly demonstrates the crucial role of genetic defects in the pathogenesis of DCM, and over 100 culprit genes have been implicated with DCM. However, DCM is of substantial genetic heterogeneity, and the genetic determinants underpinning DCM remain largely elusive. Methods Whole-exome sequencing and bioinformatical analyses were implemented in a consanguineous Chinese family with DCM. A total of 380 clinically annotated control individuals and 166 more DCM index cases then underwent Sanger sequencing analysis for the identified genetic variation. The functional characteristics of the variant were delineated by utilizing a dual-luciferase assay system. Results A heterozygous variation in the MEF2A gene (encoding myocyte enhancer factor 2A, a transcription factor pivotal for embryonic cardiogenesis and postnatal cardiac adaptation), NM_001365204.1: c.718G>T; p. (Gly240*), was identified, and verified by Sanger sequencing to segregate with autosome-dominant DCM in the family with complete penetrance. The nonsense variation was neither detected in 760 control chromosomes nor found in 166 more DCM probands. Functional analyses revealed that the variant lost transactivation on the validated target genes MYH6 and FHL2, both causally linked to DCM. Furthermore, the variation nullified the synergistic activation between MEF2A and GATA4, another key transcription factor involved in DCM. Conclusions The findings firstly indicate that MEF2A loss-of-function variation predisposes to DCM in humans, providing novel insight into the molecular mechanisms of DCM and suggesting potential implications for genetic testing and prognostic evaluation of DCM patients.
- Published
- 2020
5. Identification of BMP10 as a Novel Gene Contributing to Dilated Cardiomyopathy.
- Author
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Gu, Jia-Ning, Yang, Chen-Xi, Ding, Yuan-Yuan, Qiao, Qi, Di, Ruo-Min, Sun, Yu-Min, Wang, Jun, Yang, Ling, Xu, Ying-Jia, and Yang, Yi-Qing
- Subjects
DILATED cardiomyopathy ,GENETIC variation ,CHINESE people ,MYOCARDIUM ,CONGESTIVE heart failure - Abstract
Dilated cardiomyopathy (DCM), characterized by left ventricular or biventricular enlargement with systolic dysfunction, is the most common type of cardiac muscle disease. It is a major cause of congestive heart failure and the most frequent indication for heart transplantation. Aggregating evidence has convincingly demonstrated that DCM has an underlying genetic basis, though the genetic defects responsible for DCM in a larger proportion of cases remain elusive, motivating the ongoing research for new DCM-causative genes. In the current investigation, a multigenerational family affected with autosomal-dominant DCM was recruited from the Chinese Han population. By whole-exome sequencing and Sanger sequencing analyses of the DNAs from the family members, a new BMP10 variation, NM_014482.3:c.166C > T;p.(Gln56*), was discovered and verified to be in co-segregation with the DCM phenotype in the entire family. The heterozygous BMP10 variant was not detected in 268 healthy volunteers enrolled as control subjects. The functional measurement via dual-luciferase reporter assay revealed that Gln56*-mutant BMP10 lost the ability to transactivate its target genes NKX2.5 and TBX20, two genes that had been causally linked to DCM. The findings strongly indicate BMP10 as a new gene contributing to DCM in humans and support BMP10 haploinsufficiency as an alternative pathogenic mechanism underpinning DCM, implying potential implications for the early genetic diagnosis and precision prophylaxis of DCM. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
6. Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy
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Hong-Yu Shi, Ruo-Gu Li, Jiahong Xu, Hua Liu, Hong Zhang, Xin-Kai Qu, Ying-Jia Xu, Yu-Han Guo, Xing-Biao Qiu, Jian-Yun Gu, Yi-Qing Yang, and Xiaoxiao Yang
- Subjects
Cardiomyopathy, Dilated ,Male ,0301 basic medicine ,China ,Genotype ,TBX20 ,DNA Mutational Analysis ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Polymerase Chain Reaction ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Genes, Reporter ,Prevalence ,medicine ,Humans ,cardiovascular diseases ,Age of Onset ,Gene ,Transcription factor ,Genetics ,Mutation ,business.industry ,GATA4 ,Dilated cardiomyopathy ,DNA ,General Medicine ,Middle Aged ,medicine.disease ,Pedigree ,030104 developmental biology ,Heart failure ,Homeobox Protein Nkx-2.5 ,cardiovascular system ,Female ,Cardiology and Cardiovascular Medicine ,business ,Follow-Up Studies - Abstract
Dilated cardiomyopathy (DCM), the most common form of primary myocardial disease, is a leading cause of congestive heart failure and the most common indication for heart transplantation. Recently, NKX2-5 mutations have been involved in the pathogenesis of familial DCM. However, the prevalence and spectrum of NKX2-5 mutations associated with sporadic DCM remain to be evaluated. In this study, the coding regions and flanking introns of the NKX2-5 gene, which encodes a cardiac transcription factor pivotal for cardiac development and structural remodeling, were sequenced in 210 unrelated patients with sporadic adult-onset DCM. A total of 300 unrelated healthy individuals used as controls were also genotyped for NKX2-5. The functional effect of the mutant NKX2-5 was investigated using a dual-luciferase reporter assay system. As a result, two novel heterozygous NKX2-5 mutations, p.R139W and p.E167X, were identified in 2 unrelated patients with sporadic adult-onset DCM, with a mutational prevalence of approximately 0.95%. The mutations were absent in 600 referential chromosomes and the altered amino acids were completely conserved evolutionarily across species. Functional assays revealed that the NKX2-5 mutants were associated with significantly reduced transcriptional activity. Furthermore, the mutations abrogated the synergistic activation between NKX2-5 and GATA4 as well as TBX20, two other cardiac key transcription factors that have been causally linked to adult-onset DCM. This study is the first to associate NKX2-5 loss-of-function mutations with enhanced susceptibility to sporadic DCM, which provides novel insight into the molecular etiology underpinning DCM, and suggests the potential implications for the genetic counseling and personalized treatment of the DCM patients.
- Published
- 2017
7. Detection and functional characterization of a novel MEF2A variation responsible for familial dilated cardiomyopathy.
- Author
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Qiao, Qi, Zhao, Cui-Mei, Yang, Chen-Xi, Gu, Jia-Ning, Guo, Yu-Han, Zhang, Min, Li, Ruo-Gu, Qiu, Xing-Biao, Xu, Ying-Jia, and Yang, Yi-Qing
- Subjects
DILATED cardiomyopathy ,GENETIC testing ,GENES ,TRANSCRIPTION factors ,HEART failure - Abstract
Dilated cardiomyopathy (DCM) represents the most frequent form of cardiomyopathy, leading to heart failure, cardiac arrhythmias and death. Accumulating evidence convincingly demonstrates the crucial role of genetic defects in the pathogenesis of DCM, and over 100 culprit genes have been implicated with DCM. However, DCM is of substantial genetic heterogeneity, and the genetic determinants underpinning DCM remain largely elusive. Whole-exome sequencing and bioinformatical analyses were implemented in a consanguineous Chinese family with DCM. A total of 380 clinically annotated control individuals and 166 more DCM index cases then underwent Sanger sequencing analysis for the identified genetic variation. The functional characteristics of the variant were delineated by utilizing a dual-luciferase assay system. A heterozygous variation in the MEF2A gene (encoding myocyte enhancer factor 2A, a transcription factor pivotal for embryonic cardiogenesis and postnatal cardiac adaptation), NM_001365204.1: c.718G>T; p. (Gly240*), was identified, and verified by Sanger sequencing to segregate with autosome-dominant DCM in the family with complete penetrance. The nonsense variation was neither detected in 760 control chromosomes nor found in 166 more DCM probands. Functional analyses revealed that the variant lost transactivation on the validated target genes MYH6 and FHL2, both causally linked to DCM. Furthermore, the variation nullified the synergistic activation between MEF2A and GATA4, another key transcription factor involved in DCM. The findings firstly indicate that MEF2A loss-of-function variation predisposes to DCM in humans, providing novel insight into the molecular mechanisms of DCM and suggesting potential implications for genetic testing and prognostic evaluation of DCM patients. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
8. 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
- Subjects
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
9. TBX5 loss-of-function mutation contributes to familial dilated cardiomyopathy
- Author
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Xing-Biao Qiu, Ying-Jia Xu, Lei Xu, Yi-Qing Yang, Xian-Ling Zhang, Xu-Min Hou, Juan Wang, Cui-Mei Zhao, Ruo-Gu Li, Xin-Kai Qu, Fang Yuan, Hong-Yu Shi, and Yawei Xu
- Subjects
Adult ,Cardiomyopathy, Dilated ,Male ,Molecular Sequence Data ,Mutant ,Dilated cardiomyopathy ,Biophysics ,Biology ,Biochemistry ,Cohort Studies ,Exon ,Genetics ,medicine ,Humans ,Missense mutation ,Amino Acid Sequence ,Molecular Biology ,Aged ,Homeodomain Proteins ,GATA4 ,Intron ,Cell Biology ,Middle Aged ,medicine.disease ,TBX5 ,Penetrance ,GATA4 Transcription Factor ,Reporter gene assay ,Mutation ,Mutation (genetic algorithm) ,Homeobox Protein Nkx-2.5 ,cardiovascular system ,Female ,Transcription factor ,T-Box Domain Proteins ,Transcription Factors - Abstract
The cardiac T-box transcription factor TBX5 is crucial for proper cardiovascular development, and mutations in TBX5 have been associated with various congenital heart diseases and arrhythmias in humans. However, whether mutated TBX5 contributes to dilated cardiomyopathy (DCM) remains unclear. In this study, the coding exons and flanking introns of the TBX5 gene were sequenced in 190 unrelated patients with idiopathic DCM. The available family members of the index patient carrying an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped for TBX5. The functional characteristics of the mutant TBX5 were explored in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.S154A, was identified in a family with DCM inherited in an autosomal dominant pattern, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily across various species. Functional assays revealed that the mutant TBX5 had significantly decreased transcriptional activity. Furthermore, the mutation markedly diminished the synergistic activation of TBX5 with NKX2-5 or GATA4, other two transcription factors causatively linked to DCM. This study firstly associates TBX5 loss-of-function mutation with enhanced susceptibility to DCM, providing novel insight into the molecular mechanisms of DCM, and suggesting the potential implications in the development of new treatment strategies for this common form of myocardial disorder.
- Published
- 2015
10. A novel NKX2-5 loss-of-function mutation predisposes to familial dilated cardiomyopathy and arrhythmias
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Xu Liu, Xing-Biao Qiu, Yi-Qing Yang, De-Ning Liao, Ying-Jia Xu, Xin-Kai Qu, Fang Yuan, Juan Wang, Ruo-Gu Li, and Wei-Yi Fang
- Subjects
Adult ,Cardiomyopathy, Dilated ,Male ,Mutant ,Mutation, Missense ,Cardiomyopathy ,Biology ,Genetics ,medicine ,Humans ,Missense mutation ,cardiovascular diseases ,Homeodomain Proteins ,Genetic heterogeneity ,Autosomal dominant trait ,Arrhythmias, Cardiac ,Dilated cardiomyopathy ,General Medicine ,Middle Aged ,medicine.disease ,Penetrance ,Case-Control Studies ,Mutation (genetic algorithm) ,Homeobox Protein Nkx-2.5 ,cardiovascular system ,Female ,Transcription Factors - Abstract
Dilated cardiomyopathy (DCM) is the most prevalent type of primary myocardial disease, which is the third most common cause of heart failure and the most frequent reason for heart transplantation. Aggregating evidence demonstrates that genetic risk factors are involved in the pathogenesis of idiopathic DCM. Nevertheless, DCM is of remarkable genetic heterogeneity and the genetic defects underpinning DCM in an overwhelming majority of patients remain unknown. In the present study, the whole coding exons and splice junction sites of the NKX2-5 gene, which encodes a homeodomain transcription factor crucial for cardiac development and structural remodeling, were sequenced in 130 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped for the NKX2-5 gene. The functional effect of the mutant NKX2-5 was characterized in contrast to its wild-type counterpart using a dual-luciferase reporter assay system. As a result, a novel heterozygous NKX2-5 mutation, p.S146W, was identified in a family with DCM inherited as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. Notably, the mutation carriers also had arrhythmias, such as paroxysmal atrial fibrillation and atrioventricular block. The missense mutation was absent in 400 reference chromosomes and the altered amino acid was completely conserved evolutionarily among species. Functional analysis revealed that the NKX2-5 mutant was associated with a significantly reduced transcriptional activity. The findings expand the mutational spectrum of NKX2-5 linked to DCM and provide novel insight into the molecular mechanisms underlying DCM, contributing to the antenatal prophylaxis and allele-specific management of DCM.
- Published
- 2014
11. ZBTB17 loss-of-function mutation contributes to familial dilated cardiomyopathy
- Author
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Xin-Hua Wang, Ruo-Gu Li, Yi-Qing Yang, Liang Zhao, Xin-Kai Qu, Xing-Biao Qiu, Min Zhang, Hong-Yu Shi, Yan-Jie Li, Yu-Min Sun, Jun Wang, Ying-Jia Xu, Hua Liu, and Fang Yuan
- Subjects
0301 basic medicine ,Proband ,Cardiomyopathy, Dilated ,Male ,Heterozygote ,Genetic counseling ,Nonsense mutation ,DNA Mutational Analysis ,Kruppel-Like Transcription Factors ,030204 cardiovascular system & hematology ,Polymerase Chain Reaction ,03 medical and health sciences ,0302 clinical medicine ,Mutation Carrier ,medicine ,Humans ,Genetic Predisposition to Disease ,cardiovascular diseases ,Genetics ,Genetic heterogeneity ,business.industry ,Dilated cardiomyopathy ,Zinc Fingers ,DNA ,Exons ,Middle Aged ,musculoskeletal system ,medicine.disease ,Penetrance ,Pedigree ,030104 developmental biology ,Mutation (genetic algorithm) ,Mutation ,cardiovascular system ,Female ,Cardiology and Cardiovascular Medicine ,business - Abstract
Dilated cardiomyopathy (DCM) is a common primary myocardial disease leading to congestive heart failure, arrhythmia and sudden cardiac death. Increasing studies demonstrate substantial genetic determinants for DCM. Nevertheless, DCM is of substantial genetic heterogeneity, and the genetic basis for DCM in most patients remains unclear. The present study was sought to investigate the association of a genetic variant in the ZBTB17 gene with DCM. A cohort of 158 unrelated patients with idiopathic DCM and a total of 230 unrelated, ethnically matched healthy individuals used as controls were recruited. The coding exons and splicing boundaries of ZBTB17 were sequenced in all study participants. The functional effect of the mutant ZBTB17 was characterized by a dual-luciferase reporter assay system. A novel heterozygous ZBTB17 mutation, p.E243X, was discovered in an index patient. Genetic scan of the mutation carrier's available relatives showed that the mutation was present in all affected family members but absent in unaffected family members. Analysis of the proband's pedigree revealed that the mutation co-segregated with DCM, which was transmitted in an autosomal dominant pattern with complete penetrance. The nonsense mutation was absent in the 460 control chromosomes. Functional assays demonstrated that the truncated ZBTB17 protein had no transcriptional activity as compared with its wild-type counterpart. This study firstly associates ZBTB17 loss-of-function mutation with enhanced susceptibility to DCM in humans, which provides novel insight into the molecular mechanism underpinning DCM, implying potential implications for genetic counseling and personalized management of DCM.
- Published
- 2017
12. GATA6 loss-of-function mutations contribute to familial dilated cardiomyopathy
- Author
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Xin-Kai Qu, Yi-Qing Yang, Lei Xu, Ying-Jia Xu, Wei-Yi Fang, Fang Yuan, Wei-Feng Jiang, Hua Liu, Xing-Biao Qiu, Lan Zhao, Min Zhang, and Ruo-Gu Li
- Subjects
Adult ,Cardiomyopathy, Dilated ,Male ,Transcriptional Activation ,Heterozygote ,Molecular Sequence Data ,Mutation, Missense ,Biology ,Bioinformatics ,medicine.disease_cause ,Exon ,GATA6 Transcription Factor ,Genetics ,medicine ,Humans ,Missense mutation ,Genetic Predisposition to Disease ,Amino Acid Sequence ,Prospective Studies ,cardiovascular diseases ,Loss function ,Aged ,Mutation ,Genetic heterogeneity ,Dilated cardiomyopathy ,Exons ,Sequence Analysis, DNA ,General Medicine ,Middle Aged ,musculoskeletal system ,medicine.disease ,Penetrance ,Introns ,Pedigree ,Transplantation ,cardiovascular system ,Female ,Sequence Alignment - Abstract
Dilated cardiomyopathy (DCM), the most prevalent form of primary heart muscle disease, is the third most common cause of heart failure and the most frequent reason for cardiac transplantation. Mounting evidence has demonstrated that genetic risk factors are crucial in the pathogenesis of DCM. However, DCM is genetically heterogeneous, and the genetic basis of DCM in a large majority of cases remains unclear. In the current study, the coding exons and flanking introns of the GATA6 gene, which encodes a zinc‑finger transcription factor essential for cardiogenesis, was sequenced in 140 unrelated patients with DCM, and two novel heterozygous mutations, p.C447Y and p.H475R, were identified in two index patients with DCM, respectively. Analysis of the pedigrees showed that in each family the mutation co-segregated with DCM transmitted in an autosomal-dominant pattern, with complete penetrance. The missense mutations were absent in 400 control chromosomes and predicted to be disease-causing by MutationTaster or probably damaging by PolyPhen-2. The alignment of multiple GATA6 proteins across species revealed that the altered amino acids were completely conserved evolutionarily. The functional assays showed that the mutated GATA6 proteins were associated with significantly reduced transcriptional activation in comparison with their wild-type counterpart. To the best of our knowledge, this is the first study on the association of GATA6 loss-of-function mutations with enhanced susceptibility to familial DCM, which provides novel insight into the molecular mechanism of DCM and suggests potential implications for the antenatal prophylaxis and allele-specific treatment of DCM.
- Published
- 2014
13. A novel TBX20 loss‑of‑function mutation contributes to adult‑onset dilated cardiomyopathy or congenital atrial septal defect
- Author
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Xing‑Biao Qiu, Yi‑Meng Zhou, Yi-Qing Yang, Ri‑Tai Huang, Song Xue, Xiao‑Yong Dai, and Ying‑Jia Xu
- Subjects
0301 basic medicine ,Adult ,Cardiomyopathy, Dilated ,Male ,Cancer Research ,Heterozygote ,TBX20 ,Nonsense mutation ,Mutation, Missense ,Biology ,Biochemistry ,Heart Septal Defects, Atrial ,Primary cardiomyopathy ,03 medical and health sciences ,Mutation Carrier ,Genetics ,medicine ,Humans ,Point Mutation ,Genetic Predisposition to Disease ,cardiovascular diseases ,Molecular Biology ,Genetic heterogeneity ,Point mutation ,Dilated cardiomyopathy ,Middle Aged ,medicine.disease ,GATA4 Transcription Factor ,030104 developmental biology ,Oncology ,Case-Control Studies ,Mutation (genetic algorithm) ,cardiovascular system ,Homeobox Protein Nkx-2.5 ,Molecular Medicine ,Female ,T-Box Domain Proteins - Abstract
Dilated cardiomyopathy (DCM) is the most prevalent form of primary cardiomyopathy in humans and is a leading cause of heart failure and sudden cardiac death. Genetic abnormalities have been demonstrated to be a major contributor to the development of DCM. However, DCM is a genetically heterogeneous disease, and the genetic basis underlying DCM in a significant proportion of patients remains unclear. In the current study, the coding exons and splicing junction sites of the T‑Box 20 (TBX20) gene, which encodes a T‑box transcription factor essential for cardiac morphogenesis and structural remodeling, were sequenced in 115 unrelated patients with idiopathic DCM, and a novel heterozygous mutation, p.E143X, was identified in one patient. Genetic analysis of the mutation carrier's pedigree indicated that the nonsense mutation was present in all the living family members with DCM, and also in a female patient with a congenital atrial septal defect. The mutation, which was predicted to generate a truncated protein with only the N‑terminus and a fraction of the T‑box domain remaining, was absent in 800 control chromosomes. Functional assays using a dual‑luciferase reporter assay system revealed that the truncated TBX20 protein had no transcriptional activity in contrast to its wild‑type counterpart. Furthermore, the mutation abolished the synergistic activation between TBX20 and NK2 homeobox 5, or between TBX20 and GATA binding protein 4. The observations of the current study expand the mutation spectrum of TBX20 associated with DCM and congenital heart disease (CHD), which provide novel insight into the molecular mechanisms underlying DCM and CHD, suggesting the potential implications for the effective and personalized treatment of these diseases.
- Published
- 2015
14. CASZ1 loss-of-function mutation contributes to familial dilated cardiomyopathy.
- Author
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Xing-Biao Qiu, Xin-Kai Qu, Ruo-Gu Li, Hua Liu, Ying-Jia Xu, Min Zhang, Hong-Yu Shi, Xu-Min Hou, Xu Liu, Song Xue, Fang Yuan, Yu-Min Sun, Jun Wang, Ri-Tai Huang, and Yi-Qing Yang
- Subjects
ZINC-finger proteins ,DILATED cardiomyopathy ,GENETICS ,GENE expression ,TRANSCRIPTION factors - Abstract
Background: The zinc finger transcription factor CASZ1 plays a key role in cardiac development and postnatal adaptation, and in mice, deletion of the CASZ1 gene leads to dilated cardiomyopathy (DCM). However, in humans whether genetically defective CASZ1 contributes to DCM remains unclear. Methods: The coding exons and splicing junction sites of the CASZ1 gene were sequenced in 138 unrelated patients with idiopathic DCM. The available family members of the index patient harboring an identified CASZ1 mutation and 200 unrelated, ethnically matched healthy individuals used as controls were genotyped for CASZ1. The functional characteristics of the mutant CASZ1 were analyzed in contrast to its wild-type counterpart using a luciferase reporter assay system. Results: A novel heterozygous CASZ1 mutation, p.K351X, was identified in an index patient with DCM. Genetic analysis of the mutation carrier's family showed that the mutation co-segregated with DCM, which was transmitted in an autosomal dominant pattern with complete penetrance. The nonsense mutation, which was absent in 400 referential chromosomes, altered the amino acid that was highly conserved evolutionarily. Biological investigations revealed that the mutant CASZ1 had no transcriptional activity. Conclusions: The current study reveals CASZ1 as a new gene responsible for human DCM, which provides novel mechanistic insight and potential therapeutic target for CASZ1-associated DCM, implying potential implications in improved prophylactic and therapeutic strategies for DCM, the most common type of primary myocardial disease. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
15. A novel TBX20 loss-of-function mutation contributes to adult-onset dilated cardiomyopathy or congenital atrial septal defect.
- Author
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YI-MENG ZHOU, XIAO-YONG DAI, RI-TAI HUANG, SONG XUE, YING-JIA XU, XING-BIAO QIU, and YI-QING YANG
- Subjects
DILATED cardiomyopathy ,HEART failure ,CARDIAC arrest ,GENETICS ,MEDICINE - Abstract
Dilated cardiomyopathy (DCM) is the most prevalent form of primary cardiomyopathy in humans and is a leading cause of heart failure and sudden cardiac death. Genetic abnormalities have been demonstrated to be a major contributor to the development of DCM. However, DCM is a genetically heterogeneous disease, and the genetic basis underlying DCM in a significant proportion of patients remains unclear. In the current study, the coding exons and splicing junction sites of the T-Box 20 (TBX20) gene, which encodes a T-box transcription factor essential for cardiac morphogenesis and structural remodeling, were sequenced in 115 unrelated patients with idiopathic DCM, and a novel heterozygous mutation, p.E143X, was identified in one patient. Genetic analysis of the mutation carrier's pedigree indicated that the nonsense mutation was present in all the living family members with DCM, and also in a female patient with a congenital atrial septal defect. The mutation, which was predicted to generate a truncated protein with only the N-terminus and a fraction of the T-box domain remaining, was absent in 800 control chromosomes. Functional assays using a dual-luciferase reporter assay system revealed that the truncated TBX20 protein had no transcriptional activity in contrast to its wild-type counterpart. Furthermore, the mutation abolished the synergistic activation between TBX20 and NK2 homeobox 5, or between TBX20 and GATA binding protein 4. The observations of the current study expand the mutation spectrum of TBX20 associated with DCM and congenital heart disease (CHD), which provide novel insight into the molecular mechanisms underlying DCM and CHD, suggesting the potential implications for the effective and personalized treatment of these diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
16. HAND1 loss-of-function mutation associated with familial dilated cardiomyopathy.
- Author
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Yi-Meng Zhoua, Xiao-Yong Dai, Xing-Biao Qiu, Fang Yuan, Ruo-Gu Li, Ying-Jia Xu, Xin-Kai Qu, Ri-Tai Huang, Song Xue, and Yi-Qing Yang
- Subjects
HELIX-loop-helix motifs ,TRANSCRIPTION factors ,GENETIC mutation ,DILATED cardiomyopathy ,CONGENITAL heart disease ,GENETICS - Abstract
Background: The basic helix-loop-helix transcription factor HAND1 is essential for cardiac development and structural remodeling, and mutations in HAND1 have been causally linked to various congenital heart diseases. However, whether genetically compromised HAND1 predisposes to dilated cardiomyopathy (DCM) in humans remains unknown. Methods: The whole coding region and splicing junctions of the HAND1 gene were sequenced in 140 unrelated patients with idiopathic DCM. The available family members of the index patient carrying an identified mutation and 260 unrelated ethnically matched healthy individuals used as controls were genotyped for HAND1. The functional effect of the mutant HAND1 was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system. Results: A novel heterozygous HAND1 mutation, p.R105X, was identified in a family with DCM transmitted as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The nonsense mutation was absent in 520 control chromosomes. Functional analyses unveiled that the mutant HAND1 had no transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND1 and GATA4, another crucial cardiac transcription factors that has been associated with various congenital cardiovascular malformations and DCM. Conclusions: This study firstly reports the association of HAND1 loss-of-function mutation with increased susceptibility to DCM in humans, which provides novel insight into the molecular mechanisms underpinning DCM. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
17. Prevalence and spectrum of LRRC10 mutations associated with idiopathic dilated cardiomyopathy.
- Author
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XIN-KAI QU, FANG YUAN, RUO-GU LI, LEI XU, WEI-FENG JING, HUA LIU, YING-JIA XU, MIN ZHANG, XU LIU, WEI-YI FANG, YI-QING YANG, and XING-BIAO QIU
- Subjects
DILATED cardiomyopathy ,MISSENSE mutation ,DISEASE prevalence ,LEUCINE ,GENOTYPES ,PROTEIN expression ,GENETICS - Abstract
Dilated cardiomyopathy (DCM) is the most common form of primary myocardial disease. It is the most common cause of chronic congestive heart failure and the most frequent reason for heart transplantation in young adults. There is increasing evidence demonstrating that genetic defects are involved in the pathogenesis of idiopathic DCM. Recent studies have shown that genetically defective LRRC10 predisposes animals to DCM. However, the association of LRRC10 with DCM in humans has not been reported. In the current study, the whole coding region and flanking splice junction sites of the LRRC10 gene were sequenced in 220 unrelated patients with idiopathic DCM. The available relatives of the index patients harboring identified mutations and 200 unrelated ethnically matched healthy individuals used as controls were also genotyped for LRRC10. The functional effect of the LRRC10 mutations was analyzed in silico. As a result, two novel heterozygous LRRC10 mutations, p.L41V and p.L163I, were identified in two families with DCM, respectively, with a mutational prevalence of ~0.91%. Genetic analyses of the pedigrees showed that in each family, the mutation co-segregated with DCM was transmitted as an autosomal dominant trait with complete penetrance. The missense mutations were absent in 400 control chromosomes and the altered amino acids were completely conserved evolutionarily across various species. Functional analysis in silico indicated that the LRRC10 mutations were causative. This study firstly reports the association of LRRC10 mutations with enhanced susceptibility to DCM in humans, which provides novel insight into the molecular mechanism underpinning DCM, and contributes to the development of novel prophylactic and therapeutic strategies for DCM. [ABSTRACT FROM AUTHOR]
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- 2015
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18. GATA4 loss-of-function mutation underlies familial dilated cardiomyopathy
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Xu Liu, Li Li, Xin Li, Min Zhang, Xing-Biao Qiu, Ying-Jia Xu, Ruo-Gu Li, Luying Peng, Xin-Kai Qu, Lei Xu, Fang Yuan, Wei-Feng Jiang, Yi-Qing Yang, Jin-Qi Jiang, and Wei-Yi Fang
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Adult ,Cardiomyopathy, Dilated ,Male ,Mutant ,Biophysics ,Dilated cardiomyopathy ,Biology ,medicine.disease_cause ,Biochemistry ,GATA4 ,medicine ,Genetics ,Humans ,Missense mutation ,Genetic Predisposition to Disease ,Molecular Biology ,Gene ,Homeodomain Proteins ,Mutation ,Autosomal dominant trait ,Cell Biology ,Middle Aged ,medicine.disease ,Penetrance ,GATA4 Transcription Factor ,NKX2-5 ,Homeobox Protein Nkx-2.5 ,Cancer research ,cardiovascular system ,Female ,Transcription factor ,Transcription Factors - Abstract
The cardiac transcription factor GATA4 is essential for cardiac development, and mutations in this gene have been implicated in a wide variety of congenital heart diseases in both animal models and humans. However, whether mutated GATA4 predisposes to dilated cardiomyopathy (DCM) remains unknown. In this study, the whole coding region and splice junction sites of the GATA4 gene was sequenced in 110 unrelated patients with idiopathic DCM. The available relatives of the index patient harboring an identified mutation and 200 unrelated ethnically matched healthy individuals used as controls were genotyped. The functional effect of the mutant GATA4 was characterized in contrast to its wild-type counterpart using a luciferase reporter assay system. As a result, a novel heterozygous GATA4 mutation, p.C271S, was identified in a family with DCM inherited as an autosomal dominant trait, which co-segregated with DCM in the family with complete penetrance. The missense mutation was absent in 400 control chromosomes and the altered amino acid was completely conserved evolutionarily among species. Functional analysis demonstrated that the GATA4 mutant was associated with significantly decreased transcriptional activity and remarkably reduced synergistic activation between GATA4 and NKX2-5, another transcription factor crucial for cardiogenesis. The findings provide novel insight into the molecular mechanisms involved in the pathogenesis of DCM, suggesting the potential implications in the prenatal diagnosis and gene-specific treatment for this common form of myocardial disorder.
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19. 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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DILATED cardiomyopathy , *MUTANT proteins , *TRANSCRIPTION factors , *VENTRICULAR remodeling , *NONSENSE mutation , *RNA splicing , *RECESSIVE genes - 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, t he 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. [ABSTRACT FROM AUTHOR]
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- 2019
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20. KLF13 Loss‐of‐Function Mutations Underlying Familial Dilated Cardiomyopathy
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Yu‐Han Guo, Jun Wang, Xiao‐Juan Guo, Ri‐Feng Gao, Chen‐Xi Yang, Li Li, Yu‐Min Sun, Xing‐Biao Qiu, Ying‐Jia Xu, and Yi‐Qing Yang
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biological assay ,dilated cardiomyopathy ,functional genomics ,KLF13 ,molecular genetics ,transcriptional factor ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background Dilated cardiomyopathy (DCM), characterized by progressive left ventricular enlargement and systolic dysfunction, is the most common type of cardiomyopathy and a leading cause of heart failure and cardiac death. Accumulating evidence underscores the critical role of genetic defects in the pathogenesis of DCM, and >250 genes have been implicated in DCM to date. However, DCM is of substantial genetic heterogeneity, and the genetic basis underpinning DCM remains elusive in most cases. Methods and Results By genome‐wide scan with microsatellite markers and genetic linkage analysis in a 4‐generation family inflicted with autosomal‐dominant DCM, a new locus for DCM was mapped on chromosome 15q13.1–q13.3, a 4.77‐cM (≈3.43 Mbp) interval between markers D15S1019 and D15S1010, with the largest 2‐point logarithm of odds score of 5.1175 for the marker D15S165 at recombination fraction (θ)=0.00. Whole‐exome sequencing analyses revealed that within the mapping chromosomal region, only the mutation in the KLF13 gene, c.430G>T (p.E144X), cosegregated with DCM in the family. In addition, sequencing analyses of KLF13 in another cohort of 266 unrelated patients with DCM and their available family members unveiled 2 new mutations, c.580G>T (p.E194X) and c.595T>C (p.C199R), which cosegregated with DCM in 2 families, respectively. The 3 mutations were absent from 418 healthy subjects. Functional assays demonstrated that the 3 mutants had no transactivation on the target genes ACTC1 and MYH7 (2 genes causally linked to DCM), alone or together with GATA4 (another gene contributing to DCM), and a diminished ability to bind the promoters of ACTC1 and MYH7. Add, the E144X‐mutant KLF13 showed a defect in intracellular distribution. Conclusions This investigation indicates KLF13 as a new gene predisposing to DCM, which adds novel insight to the molecular pathogenesis underlying DCM, implying potential implications for prenatal prevention and precision treatment of DCM in a subset of patients.
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- 2022
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21. VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
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Shi, Hong-Yu, Xie, Meng-Shi, Guo, Yu-Han, Yang, Chen-Xi, Gu, Jia-Ning, Qiao, Qi, Di, Ruo-Min, Qiu, Xing-Biao, Xu, Ying-Jia, and Yang, Yi-Qing
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DILATED cardiomyopathy , *GENETIC mutation , *NONSENSE mutation , *CARDIAC arrest , *SINGLE nucleotide polymorphisms , *SUDDEN death , *DATABASES - Abstract
Dilated cardiomyopathy (DCM), characteristic of left ventricular or biventricular dilation with systolic dysfunction, is the most common form of cardiomyopathy, and a leading cause of heart failure and sudden cardiac death. Aggregating evidence highlights the underlying genetic basis of DCM, and mutations in over 100 genes have been causally linked to DCM. Nevertheless, due to pronounced genetic heterogeneity, the genetic defects underpinning DCM in most cases remain obscure. Hence, this study was sought to identify novel genetic determinants of DCM. In this investigation, whole-exome sequencing and bioinformatics analyses were conducted in a family suffering from DCM, and a novel heterozygous mutation in the VEZF1 gene (coding for a zinc finger-containing transcription factor critical for cardiovascular development and structural remodeling), NM_007146.3: c.490A > T; p.(Lys164*), was identified. The nonsense mutation was validated by Sanger sequencing and segregated with autosome-dominant DCM in the family with complete penetrance. The mutation was neither detected in another cohort of 200 unrelated DCM patients nor observed in 400 unrelated healthy individuals nor retrieved in the Single Nucleotide Polymorphism database, the Human Gene Mutation Database and the Genome Aggregation Database. Biological analyses by utilizing a dual-luciferase reporter assay system revealed that the mutant VEZF1 protein failed to transactivate the promoters of MYH7 and ET1 , two genes that have been associated with DCM. The findings indicate VEZF1 as a new gene responsible for DCM, which provides novel insight into the molecular pathogenesis of DCM, implying potential implications for personalized precisive medical management of the patients affected with DCM. [ABSTRACT FROM AUTHOR]
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- 2023
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22. GATA4 loss-of-function mutation underlies familial dilated cardiomyopathy.
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Li, Ruo-Gu, Li, Li, Qiu, Xing-Biao, Yuan, Fang, Xu, Lei, Li, Xin, Xu, Ying-Jia, Jiang, Wei-Feng, Jiang, Jin-Qi, Liu, Xu, Fang, Wei-Yi, Zhang, Min, Peng, Lu-Ying, Qu, Xin-Kai, and Yang, Yi-Qing
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TRANSCRIPTION factors , *DILATED cardiomyopathy , *GENETIC mutation , *GENE expression , *CARDIOMYOPATHIES , *AMINO acids - Abstract
Highlights: [•] A novel GATA4 mutation, p.C271S, was identified in a large family with DCM. [•] The mutation co-segregated with DCM in the family and was absent in 200 controls. [•] The altered amino acid was completely conserved evolutionarily among species. [•] The mutant was associated with significantly decreased transcriptional activity. [•] The mutant remarkably reduced the synergistic activation between GATA4 and NKX2-5. [ABSTRACT FROM AUTHOR]
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- 2013
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23. Identification and functional characterization of KLF5 as a novel disease gene responsible for familial dilated cardiomyopathy.
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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
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DILATED cardiomyopathy , *BIOLOGICAL assay , *RNA splicing , *CARDIOMYOPATHIES , *TRANSCRIPTION factors , *NONSENSE mutation , *VIDEO coding - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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