22 results on '"Ying Jia"'
Search Results
2. ISL1 loss-of-function mutation contributes to congenital heart defects
- Author
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Ma, Lan, Wang, Juan, Li, Li, Qiao, Qi, Di, Ruo-Min, Li, Xiu-Mei, Xu, Ying-Jia, Zhang, Min, Li, Ruo-Gu, Qiu, Xing-Biao, Li, Xun, and Yang, Yi-Qing
- Published
- 2019
- Full Text
- View/download PDF
3. 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
4. PRRX1 Loss‐of‐Function Mutations Underlying Familial Atrial Fibrillation
- Author
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Chen-Xi Yang, Xing-Biao Qiu, Ying-Jia Xu, Zun-Ping Ke, Li Li, Xiao-Juan Guo, Yi-Qing Yang, Ri-Feng Gao, Ruo-Min Di, Jun Wang, Yu-Min Sun, and Yu-Han Guo
- Subjects
medical genetics ,Locus (genetics) ,medicine.disease_cause ,Genetic linkage ,medicine ,Humans ,Diseases of the circulatory (Cardiovascular) system ,Genetic Predisposition to Disease ,atrial fibrillation ,Gene ,Loss function ,Homeodomain Proteins ,Genetics ,Mutation ,business.industry ,Genetic heterogeneity ,reporter gene assay ,Atrial fibrillation ,medicine.disease ,translational regulation ,RC666-701 ,PRRX1 ,Cardiology and Cardiovascular Medicine ,business ,functional genomics ,Familial atrial fibrillation - Abstract
Background Atrial fibrillation (AF) is the most common form of clinical cardiac dysrhythmia responsible for thromboembolic cerebral stroke, congestive heart failure, and death. Aggregating evidence highlights the strong genetic basis of AF. Nevertheless, AF is of pronounced genetic heterogeneity, and in an overwhelming majority of patients, the genetic determinants underpinning AF remain elusive. Methods and Results By genome‐wide screening with polymorphic microsatellite markers and linkage analysis in a 4‐generation Chinese family affected with autosomal‐dominant AF, a novel locus for AF was mapped to chromosome 1q24.2–q25.1, a 3.20‐cM (≈4.19 Mbp) interval between markers D1S2851 and D1S218, with the greatest 2‐point logarithm of odds score of 4.8165 for the marker D1S452 at recombination fraction=0.00. Whole‐exome sequencing and bioinformatics analyses showed that within the mapping region, only the mutation in the paired related homeobox 1 ( PRRX1 ) gene, NM_022716.4:c.319C>T;(p.Gln107*), cosegregated with AF in the family. In addition, sequencing analyses of PRRX1 in another cohort of 225 unrelated patients with AF revealed a new mutation, NM_022716.4:c.437G>T; (p.Arg146Ile), in a patient. The 2 mutations were absent in 908 control subjects. Biological analyses in HeLa cells demonstrated that the 2 mutants had significantly diminished transactivation on the target genes ISL1 and SHOX2 and markedly decreased ability to bind the promoters of ISL1 and SHOX2 (2 genes causally linked to AF), although with normal intracellular distribution. Conclusions This study first indicates that PRRX1 loss‐of‐function mutations predispose to AF, which provides novel insight into the molecular pathogenesis underpinning AF, implying potential implications for precisive prophylaxis and management of AF.
- Published
- 2021
5. A SHOX2 loss-of-function mutation underlying familial atrial fibrillation
- Author
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Yi-Qing Yang, Xin-Hua Wang, Ying-Jia Xu, Xing-Biao Qiu, Ruo-Gu Li, Ruo-Min Di, Xiu-Mei Li, Ning Li, Zhang-Sheng Wang, Min Zhang, Qi Qiao, and Xiao-Juan Guo
- Subjects
0301 basic medicine ,Proband ,Male ,medicine.medical_specialty ,Genetic counseling ,Nonsense mutation ,03 medical and health sciences ,Molecular genetics ,medicine ,Humans ,Genetics ,Homeodomain Proteins ,business.industry ,Genetic heterogeneity ,General Medicine ,SHOX2 ,Middle Aged ,medicine.disease ,Penetrance ,Atrial fibrillation ,Pedigree ,Reporter gene assay ,030104 developmental biology ,HEK293 Cells ,Codon, Nonsense ,Mutation (genetic algorithm) ,Mutation ,Female ,Transcription factor ,business ,Familial atrial fibrillation ,Research Paper ,Transcription Factors - Abstract
Atrial fibrillation (AF), as the most common sustained cardiac arrhythmia, is associated with substantially increased morbidity and mortality. Aggregating evidence demonstrates that genetic defects play a crucial role in the pathogenesis of AF, especially in familial AF. Nevertheless, AF is of pronounced genetic heterogeneity, and in an overwhelming majority of cases the genetic determinants underlying AF remain elusive. In the current study, 162 unrelated patients with familial AF and 238 unrelated healthy individuals served as controls were recruited. The coding exons and splicing junction sites of the SHOX2 gene, which encodes a homeobox-containing transcription factor essential for proper development and function of the cardiac conduction system, were sequenced in all study participants. The functional effect of the mutant SHOX2 protein was characterized with a dual-luciferase reporter assay system. As a result, a novel heterozygous SHOX2 mutation, c.580C>T or p.R194X, was identified in an index patient, which was absent from the 476 control chromosomes. Genetic analysis of the proband's pedigree revealed that the nonsense mutation co-segregated with AF in the family with complete penetrance. Functional assays demonstrated that the mutant SHOX2 protein had no transcriptional activity compared with its wild-type counterpart. In conclusion, this is the first report on the association of SHOX2 loss-of-function mutation with enhanced susceptibility to familial AF, which provides novel insight into the molecular mechanism underpinning AF, suggesting potential implications for genetic counseling and individualized management of AF patients.
- Published
- 2018
6. Identification of SOX18 as a New Gene Predisposing to Congenital Heart Disease.
- Author
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Shi, Hong-Yu, Xie, Meng-Shi, Yang, Chen-Xi, Huang, Ri-Tai, Xue, Song, Liu, Xing-Yuan, Xu, Ying-Jia, and Yang, Yi-Qing
- Subjects
CONGENITAL heart disease ,GENETIC variation ,CHINESE people ,NEONATAL mortality ,HELA cells - Abstract
Congenital heart disease (CHD) is the most frequent kind of birth deformity in human beings and the leading cause of neonatal mortality worldwide. Although genetic etiologies encompassing aneuploidy, copy number variations, and mutations in over 100 genes have been uncovered to be involved in the pathogenesis of CHD, the genetic components predisposing to CHD in most cases remain unclear. We recruited a family with CHD from the Chinese Han population in the present investigation. Through whole-exome sequencing analysis of selected family members, a new SOX18 variation, namely NM_018419.3:c.349A>T; p.(Lys117*), was identified and confirmed to co-segregate with the CHD phenotype in the entire family by Sanger sequencing analysis. The heterozygous variant was absent from the 384 healthy volunteers enlisted as control individuals. Functional exploration via luciferase reporter analysis in cultivated HeLa cells revealed that Lys117*-mutant SOX18 lost transactivation on its target genes NR2F2 and GATA4, two genes responsible for CHD. Moreover, the genetic variation terminated the synergistic activation between SOX18 and NKX2.5, another gene accountable for CHD. The findings strongly indicate SOX18 as a novel gene contributing to CHD, which helps address challenges in the clinical genetic diagnosis and prenatal prophylaxis of CHD. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
7. A HAND2 Loss-of-Function Mutation Causes Familial Ventricular Septal Defect and Pulmonary Stenosis
- Author
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Fang Yuan, Song Xue, Yu-Min Sun, Jun Wang, Ruo-Gu Li, Yi-Qing Yang, Xing-Biao Qiu, Xin-Kai Qu, Ying-Jia Xu, Ri-Tai Huang, Hong-Yu Shi, and Xu-Min Hou
- Subjects
0301 basic medicine ,Proband ,Heart Septal Defects, Ventricular ,Male ,DNA Mutational Analysis ,QH426-470 ,Exon ,0302 clinical medicine ,Basic Helix-Loop-Helix Transcription Factors ,Missense mutation ,genetics ,Child ,Promoter Regions, Genetic ,Genetics (clinical) ,transcription factor ,Genetics ,GATA4 ,reporter gene assay ,congenital heart disease ,Pedigree ,Pulmonary Valve Stenosis ,030220 oncology & carcinogenesis ,Child, Preschool ,Mutation (genetic algorithm) ,Homeobox Protein Nkx-2.5 ,HAND2 ,Female ,Atrial Natriuretic Factor ,Transcriptional Activation ,Adolescent ,Biology ,Investigations ,Cell Line ,03 medical and health sciences ,Young Adult ,Double outlet right ventricle ,medicine ,Humans ,Allele ,Codon ,Molecular Biology ,Alleles ,Genetic Association Studies ,Infant, Newborn ,Infant ,medicine.disease ,GATA4 Transcription Factor ,030104 developmental biology ,Amino Acid Substitution ,Pulmonary valve stenosis ,Mutation ,Transcription Factors - Abstract
Congenital heart disease (CHD) is the most common developmental abnormality, and is the leading noninfectious cause of mortality in neonates. Increasing evidence demonstrates that genetic defects play an important role in the pathogenesis of CHD. However, CHD exhibits substantial heterogeneity, and the genetic determinants for CHD remain unknown in the overwhelming majority of cases. In the current study, the coding exons and flanking introns of the HAND2 gene, which encodes a basic helix-loop-helix transcription factor essential for normal cardiovascular development, were sequenced in 192 unrelated patients with CHD, and a novel heterozygous mutation, p.S65I, was identified in a patient with congenital ventricular septal defect (VSD). Genetic analysis of the index patient’s pedigree revealed that the mutation was present in all seven affected family members available, but absent in the 13 unaffected family members examined. Besides, in addition to VSD, five of the proband’s close relatives also had pulmonary stenosis (PS), and the proband’s son also had double outlet right ventricle (DORV). The missense mutation, which altered an evolutionarily conserved amino acid, was absent in 300 unrelated, ethnically matched healthy individuals. Biological analyses using a dual-luciferase reporter assay system showed that the mutant HAND2 was associated with significantly diminished transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND2 and GATA4, as well as NKX2.5—two other cardiac core transcriptional factors that have been causally linked to CHD. These findings indicate that HAND2 loss-of-function mutation contributes to human CHD, perhaps via its interaction with GATA4 and NKX2.5.
- Published
- 2016
8. Prevalence and Spectrum of TBX5 Mutation in Patients with Lone Atrial Fibrillation
- Author
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Wen-Hui Ji, Yi-Qing Yang, Xu Liu, Ying-Jia Xu, Song Xue, Ruo-Gu Li, Chang-Wu Ruan, Zhan-Cheng Wang, Ru-Tai Huang, Xing-Yuan Liu, Fang Yuan, and Xing-Biao Qiu
- Subjects
0301 basic medicine ,Adult ,Male ,Heterozygote ,Reporter gene assay ,Mutant ,030204 cardiovascular system & hematology ,medicine.disease_cause ,Bioinformatics ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Genetics ,Coding region ,Humans ,Genetic Predisposition to Disease ,Amino Acid Sequence ,Transcription factor ,Mutation ,GATA4 ,business.industry ,Atrial fibrillation ,General Medicine ,Middle Aged ,medicine.disease ,TBX5 ,030104 developmental biology ,RNA splicing ,Female ,business ,T-Box Domain Proteins ,Research Paper - Abstract
Atrial fibrillation (AF), the most common type of cardiac rhythm disturbance encountered in clinical practice, is associated with substantially increased morbidity and mortality. Aggregating evidence demonstrates that abnormal cardiovascular development is involved in the pathogenesis of AF. A recent study has revealed that the TBX5 gene, which encodes a T-box transcription factor key to cardiovascular development, was associated with AF and atypical Holt-Oram syndrome. However, the prevalence and spectrum of TBX5 mutation in patients with lone AF remain unclear. In this study, the coding regions and splicing junction sites of TBX5 were sequenced in 192 unrelated patients with lone AF and 300 unrelated ethnically-matched healthy individuals used as controls. The causative potential of the identified TBX5 variation was evaluated by MutationTaster and PolyPhen-2. The functional effect of the mutant TBX5 was assayed by using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.H170D, was identified in a patient, with a mutational prevalence of approximately 0.52%. This mutation, which was absent in the 300 control individuals, altered the amino acid completely conserved evolutionarily across species, and was predicted to be disease-causing. Functional deciphers showed that the mutant TBX5 was associated with significantly reduced transcriptional activity when compared with its wild-type counterpart. Furthermore, the mutation significantly decreased the synergistic activation between TBX5 and NKX2-5 or GATA4. The findings expand the mutational spectrum of TBX5 linked to AF and provide new evidence that dysfunctional TBX5 may contribute to lone AF.
- Published
- 2016
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. GATA6 loss-of-function mutation contributes to congenital bicuspid aortic valve.
- Author
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Xu, Ying-Jia, Di, Ruo-Min, Qiao, Qi, Li, Xiu-Mei, Huang, Ri-Tai, Xue, Song, Liu, Xing-Yuan, Wang, Juan, and Yang, Yi-Qing
- Subjects
- *
BICUSPIDS , *AORTIC valve , *ZINC-finger proteins , *GENETIC regulation , *DISEASE progression - Abstract
Congenital bicuspid aortic valve (BAV), the most common form of birth defect in humans, is associated with substantial morbidity and mortality. Increasing evidence demonstrates that genetic risk factors play a key role in the pathogenesis of BAV. However, BAV is a genetically heterogeneous disease and the genetic determinants underpinning BAV in an overwhelming majority of patients remain unknown. In the present study, the coding exons and flanking introns of the GATA6 gene, which encodes a zinc-finger transcription factor essential for the normal development of the aortic valves, were sequenced in 152 unrelated patients with congenital BAV. The available relatives of a proband harboring an identified GATA6 mutation and 200 unrelated, ethnically matched healthy individuals used as controls were also genotyped for GATA6 . The functional characteristics of the mutation were analyzed by using a dual-luciferase reporter assay system. As a result, a novel heterozygous GATA6 mutation, p.E386X, was identified in a family with BAV transmitted in an autosomal dominant mode. The nonsense mutation was absent in 400 control chromosomes. Biological assays revealed that the mutant GATA6 protein had no transcriptional activity compared with its wild-type counterpart. Furthermore, the mutation disrupted the synergistic transcriptional activation between GATA6 and GATA4, another transcription factor causally linked to BAV. In conclusion, this study firstly associates GATA6 loss-of-function mutation with enhanced susceptibility to familial BAV, which provides novel insight into the molecular mechanism of BAV, implying potential implications for genetic counseling and personalized management of BAV patients. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
11. 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
12. 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
- Subjects
- *
CONGENITAL heart disease , *SMAD proteins , *GENETIC variation , *RECESSIVE genes , *TRANSCRIPTION factors , *AGENESIS of corpus callosum , *HUMAN beings - 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 in >100 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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
13. 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
14. TBX5 loss-of-function mutation contributes to atrial fibrillation and atypical Holt-Oram syndrome.
- Author
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DONG-FENG GUO, RUO-GU LI, FANG YUAN, HONG-YU SHI, XU-MIN HOU, XIN-KAI QU, YING-JIA XU, MIN ZHANG, XU LIU, JIN-QI JIANG, YI-QING YANG, and XING-BIAO QIU
- Subjects
SINGLE nucleotide polymorphisms ,ATRIAL fibrillation ,HOLT-Oram syndrome ,HOMEOBOX proteins ,HOMEOBOX genes ,MISSENSE mutation - Abstract
Previous genome-wide association studies have demonstrated that single nucleotide polymorphisms in T-box (TBX)5 are associated with increased susceptibility to atrial fibrillation (AF), and a recent study has causally linked a TBX5 mutation to atypical Holt-Oram syndrome and paroxysmal AF. However, the prevalence and spectrum of TBX5 mutations in patients with AF remain to be elucidated. In the present study, a cohort of 190 unrelated patients with idiopathic AF were prospectively recruited, with 400 unrelated healthy individuals recruited as controls. The coding exons and flanking introns of the TBX5 gene were sequenced in the participants. The functional characteristics of the mutant TBX5 were delineated in contrast with its wild-type counterpart using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.P132S, was identified in an index patient with AF, with a mutational prevalence of ~0.53%. Genetic analysis of the proband's family showed that the mutation co-segregated with AF, and was transmitted in an autosomal dominant pattern. The missense mutation was absent in the 800 control chromosomes, and the altered amino acid was completely evolutionarily conserved across species. Functional analyses revealed that the mutant TBX5 had significantly reduced transcriptional activity. Furthermore, the mutation markedly decreased the synergistic activation between TBX5 and NK2 homeobox 5, another transcription factor which has been causatively linked to AF. The present study was the first, to the best of our knowledge, to report on the association between a TBX5 loss-of-function mutation and increased susceptibility to AF. These results provide novel insight into the molecular mechanism underpinning AF, and have potential implications in the development of novel prophylactic and therapeutic strategies for AF, the most common form of sustained cardiac arrhythmia. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
15. PRRX1 Loss‐of‐Function Mutations Underlying Familial Atrial Fibrillation
- Author
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Xiao‐Juan Guo, Xing‐Biao Qiu, Jun Wang, Yu‐Han Guo, Chen‐Xi Yang, Li Li, Ri‐Feng Gao, Zun‐Ping Ke, Ruo‐Min Di, Yu‐Min Sun, Ying‐Jia Xu, and Yi‐Qing Yang
- Subjects
atrial fibrillation ,functional genomics ,medical genetics ,PRRX1 ,reporter gene assay ,translational regulation ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background Atrial fibrillation (AF) is the most common form of clinical cardiac dysrhythmia responsible for thromboembolic cerebral stroke, congestive heart failure, and death. Aggregating evidence highlights the strong genetic basis of AF. Nevertheless, AF is of pronounced genetic heterogeneity, and in an overwhelming majority of patients, the genetic determinants underpinning AF remain elusive. Methods and Results By genome‐wide screening with polymorphic microsatellite markers and linkage analysis in a 4‐generation Chinese family affected with autosomal‐dominant AF, a novel locus for AF was mapped to chromosome 1q24.2–q25.1, a 3.20‐cM (≈4.19 Mbp) interval between markers D1S2851 and D1S218, with the greatest 2‐point logarithm of odds score of 4.8165 for the marker D1S452 at recombination fraction=0.00. Whole‐exome sequencing and bioinformatics analyses showed that within the mapping region, only the mutation in the paired related homeobox 1 (PRRX1) gene, NM_022716.4:c.319C>T;(p.Gln107*), cosegregated with AF in the family. In addition, sequencing analyses of PRRX1 in another cohort of 225 unrelated patients with AF revealed a new mutation, NM_022716.4:c.437G>T; (p.Arg146Ile), in a patient. The 2 mutations were absent in 908 control subjects. Biological analyses in HeLa cells demonstrated that the 2 mutants had significantly diminished transactivation on the target genes ISL1 and SHOX2 and markedly decreased ability to bind the promoters of ISL1 and SHOX2 (2 genes causally linked to AF), although with normal intracellular distribution. Conclusions This study first indicates that PRRX1 loss‐of‐function mutations predispose to AF, which provides novel insight into the molecular pathogenesis underpinning AF, implying potential implications for precisive prophylaxis and management of AF.
- Published
- 2021
- Full Text
- View/download PDF
16. Identification of SOX18 as a New Gene Predisposing to Congenital Heart Disease
- Author
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Hong-Yu Shi, Meng-Shi Xie, Chen-Xi Yang, Ri-Tai Huang, Song Xue, Xing-Yuan Liu, Ying-Jia Xu, and Yi-Qing Yang
- Subjects
cardiology ,congenital heart disease ,genetics ,transcription factor ,reporter gene assay ,Medicine (General) ,R5-920 - Abstract
Congenital heart disease (CHD) is the most frequent kind of birth deformity in human beings and the leading cause of neonatal mortality worldwide. Although genetic etiologies encompassing aneuploidy, copy number variations, and mutations in over 100 genes have been uncovered to be involved in the pathogenesis of CHD, the genetic components predisposing to CHD in most cases remain unclear. We recruited a family with CHD from the Chinese Han population in the present investigation. Through whole-exome sequencing analysis of selected family members, a new SOX18 variation, namely NM_018419.3:c.349A>T; p.(Lys117*), was identified and confirmed to co-segregate with the CHD phenotype in the entire family by Sanger sequencing analysis. The heterozygous variant was absent from the 384 healthy volunteers enlisted as control individuals. Functional exploration via luciferase reporter analysis in cultivated HeLa cells revealed that Lys117*-mutant SOX18 lost transactivation on its target genes NR2F2 and GATA4, two genes responsible for CHD. Moreover, the genetic variation terminated the synergistic activation between SOX18 and NKX2.5, another gene accountable for CHD. The findings strongly indicate SOX18 as a novel gene contributing to CHD, which helps address challenges in the clinical genetic diagnosis and prenatal prophylaxis of CHD.
- Published
- 2022
- Full Text
- View/download PDF
17. A HAND2 Loss-of-Function Mutation Causes Familial Ventricular Septal Defect and Pulmonary Stenosis
- Author
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Yu-Min Sun, Jun Wang, Xing-Biao Qiu, Fang Yuan, Ruo-Gu Li, Ying-Jia Xu, Xin-Kai Qu, Hong-Yu Shi, Xu-Min Hou, Ri-Tai Huang, Song Xue, and Yi-Qing Yang
- Subjects
congenital heart disease ,genetics ,transcription factor ,HAND2 ,reporter gene assay ,Genetics ,QH426-470 - Abstract
Congenital heart disease (CHD) is the most common developmental abnormality, and is the leading noninfectious cause of mortality in neonates. Increasing evidence demonstrates that genetic defects play an important role in the pathogenesis of CHD. However, CHD exhibits substantial heterogeneity, and the genetic determinants for CHD remain unknown in the overwhelming majority of cases. In the current study, the coding exons and flanking introns of the HAND2 gene, which encodes a basic helix-loop-helix transcription factor essential for normal cardiovascular development, were sequenced in 192 unrelated patients with CHD, and a novel heterozygous mutation, p.S65I, was identified in a patient with congenital ventricular septal defect (VSD). Genetic analysis of the index patient’s pedigree revealed that the mutation was present in all seven affected family members available, but absent in the 13 unaffected family members examined. Besides, in addition to VSD, five of the proband’s close relatives also had pulmonary stenosis (PS), and the proband’s son also had double outlet right ventricle (DORV). The missense mutation, which altered an evolutionarily conserved amino acid, was absent in 300 unrelated, ethnically matched healthy individuals. Biological analyses using a dual-luciferase reporter assay system showed that the mutant HAND2 was associated with significantly diminished transcriptional activity. Furthermore, the mutation abolished the synergistic activation between HAND2 and GATA4, as well as NKX2.5—two other cardiac core transcriptional factors that have been causally linked to CHD. These findings indicate that HAND2 loss-of-function mutation contributes to human CHD, perhaps via its interaction with GATA4 and NKX2.5.
- Published
- 2016
- Full Text
- View/download PDF
18. VEZF1 loss-of-function mutation underlying familial dilated cardiomyopathy.
- Author
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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
- Subjects
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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]
- Published
- 2023
- Full Text
- View/download PDF
19. CASZ1 loss-of-function mutation associated with congenital heart disease.
- Author
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Huang, Ri-Tai, Xue, Song, Wang, Juan, Gu, Jian-Yun, Xu, Jia-Hong, Li, Yan-Jie, Li, Ning, Yang, Xiao-Xiao, Liu, Hua, Zhang, Xiao-Dong, Qu, Xin-Kai, Xu, Ying-Jia, Qiu, Xing-Biao, Li, Ruo-Gu, and Yang, Yi-Qing
- Subjects
- *
CONGENITAL heart disease , *GENETIC mutation , *ZINC-finger proteins , *PREVENTIVE medicine , *MORTALITY , *GENETICS - Abstract
As the most common form of birth defect in humans, congenital heart disease (CHD) is associated with substantial morbidity and mortality in both children and adults. Increasing evidence demonstrates that genetic defects play a pivotal role in the pathogenesis of CHD. However, CHD is of great heterogeneity, and in an overwhelming majority of cases, the genetic determinants underpinning CHD remain elusive. In the present investigation, the coding exons and flanking introns of the CASZ1 gene, which codes for a zinc finger transcription factor essential for the cardiovascular morphogenesis, were sequenced in 172 unrelated patients with CHD. As a result, a novel heterozygous CASZ1 mutation, p.L38P, was identified in an index patient with congenital ventricular septal defect (VSD). Genetic scanning of the mutation carrier's available family members revealed that the mutation was present in all affected patients but absent in unaffected individuals. Analysis of the proband's pedigree showed that the mutation co-segregated with VSD, which was transmitted as an autosomal dominant trait with complete penetrance. The missense mutation, which altered the amino acid that was highly conserved evolutionarily, was absent in 200 unrelated, ethnically-matched healthy subjects used as controls. Functional deciphers by using a dual-luciferase reporter assay system unveiled that the mutant CASZ1 had significantly reduced transcriptional activity as compared with its wild-type counterpart. To the best of our knowledge, the current study firstly identifies CASZ1 as a new gene predisposing to CHD in humans, which provides novel insight into the molecular mechanisms underlying CHD and a potential therapeutic target for CASZ1-associated CHD, suggesting potential implications for personalized prophylaxis and therapy of CHD. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
20. PITX2 loss-of-function mutation contributes to tetralogy of Fallot.
- Author
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Sun, Yu-Min, Wang, Jun, Qiu, Xing-Biao, Yuan, Fang, Xu, Ying-Jia, Li, Ruo-Gu, Qu, Xin-Kai, Huang, Ri-Tai, Xue, Song, and Yang, Yi-Qing
- Subjects
- *
TETRALOGY of Fallot , *HOMEOBOX proteins , *TRANSCRIPTION factors , *GENETIC mutation , *INFANT diseases , *INFANT mortality , *GENOTYPES , *DIAGNOSIS - Abstract
Congenital heart disease (CHD) is the most prevalent developmental abnormality in humans and is the most common non-infectious cause of infant morbidity and mortality. Increasing evidence demonstrates that genetic defects are involved in the pathogenesis of CHD. However, CHD is genetically heterogeneous, and the genetic determinants underpinning CHD in most patients remain unknown. In this study, the whole coding region of the PITX2 gene (isoform c) was sequenced in 185 unrelated patients with CHD. The available relatives of a mutation carrier and 300 unrelated healthy individuals used as controls were also genotyped for PITX2 . The functional characteristics of the mutation were delineated by using a dual-luciferase reporter assay system. As a result, a novel heterozygous PITX2 mutation, p.Q102L, was identified in a patient with tetralogy of Fallot (TOF). Genetic analysis of the index patient's pedigree showed that the mutation co-segregated with TOF. The mutation was absent in 600 reference chromosomes. Biochemical analysis revealed that the Q102L-mutant PITX2 is associated with significantly reduced transcriptional activity compared with its wild-type counterpart. Furthermore, the mutation markedly decreased the synergistic activation between PITX2 and NKX2-5. This study firstly associates PITX2 loss-of-function mutation with increased susceptibility to TOF, providing novel insight into the molecular mechanism of CHD. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
21. 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, null, Li, Ruo-Gu, Qu, Xin-Kai, Xu, Ying-Jia, Fang, Wei-Yi, Yang, Yi-Qing, and Qiu, Xing-Biao
- Subjects
- *
CONGENITAL heart disease , *GENETIC mutation , *HUMAN abnormalities , *DISEASE prevalence , *EXONS (Genetics) , *GENETIC code , *GENETIC transcription , *PATIENTS - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
22. 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
- Subjects
- *
CONGENITAL heart disease , *GENETIC databases , *POPULATION genetics , *SINGLE nucleotide polymorphisms , *CHILDBIRTH , *RECESSIVE genes - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
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