scholarly journals NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Romaric Bouveret ◽  
Ashley J Waardenberg ◽  
Nicole Schonrock ◽  
Mirana Ramialison ◽  
Tram Doan ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Regulatory Networks ◽  
Congenital Heart ◽  
Target Genes ◽  
Loss Of Function ◽  
Wild Type ◽  
Interaction Domain ◽  
Ets Proteins ◽  
Gene Regulatory

We take a functional genomics approach to congenital heart disease mechanism. We used DamID to establish a robust set of target genes for NKX2-5 wild type and disease associated NKX2-5 mutations to model loss-of-function in gene regulatory networks. NKX2-5 mutants, including those with a crippled homeodomain, bound hundreds of targets including NKX2-5 wild type targets and a unique set of "off-targets", and retained partial functionality. NKXΔHD, which lacks the homeodomain completely, could heterodimerize with NKX2-5 wild type and its cofactors, including E26 transformation-specific (ETS) family members, through a tyrosine-rich homophilic interaction domain (YRD). Off-targets of NKX2-5 mutants, but not those of an NKX2-5 YRD mutant, showed overrepresentation of ETS binding sites and were occupied by ETS proteins, as determined by DamID. Analysis of kernel transcription factor and ETS targets show that ETS proteins are highly embedded within the cardiac gene regulatory network. Our study reveals binding and activities of NKX2-5 mutations on WT target and off-targets, guided by interactions with their normal cardiac and general cofactors, and suggest a novel type of gain-of-function in congenital heart disease.

scholarly journals Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart disease

2000 ◽  
Vol 106 (2) ◽  
pp. 299-308 ◽  
Author(s):  
Hideko Kasahara ◽  
Bora Lee ◽  
Jean-Jacques Schott ◽  
D. Woodrow Benson ◽  
J.G. Seidman ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Loss Of Function ◽  
Inhibitory Effects

scholarly journals Modeling Human TBX5 Haploinsufficiency Predicts Regulatory Networks for Congenital Heart Disease

2020 ◽  
Author(s):  
Irfan S. Kathiriya ◽  
Kavitha S. Rao ◽  
Giovanni Iacono ◽  
W. Patrick Devine ◽  
Andrew P. Blair ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Regulatory Networks ◽  
Congenital Heart

A Novel TBX1 Loss-of-Function Mutation Associated with Congenital Heart Disease

2015 ◽  
Vol 36 (7) ◽  
pp. 1400-1410 ◽  
Author(s):  
Yun Pan ◽  
Zha-Gen Wang ◽  
Xing-Yuan Liu ◽  
Hong Zhao ◽  
Ning Zhou ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Loss Of Function

CASZ1 loss-of-function mutation associated with congenital heart disease

Gene ◽  
2016 ◽  
Vol 595 (1) ◽  
pp. 62-68 ◽  
Author(s):  
Ri-Tai Huang ◽  
Song Xue ◽  
Juan Wang ◽  
Jian-Yun Gu ◽  
Jia-Hong Xu ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Loss Of Function

scholarly journals Identification and analysis of KLF13 variants in patients with congenital heart disease

2020 ◽  
Author(s):  
Wenjuan Li ◽  
Baolei Li ◽  
Tingting Li ◽  
Ergeng Zhang ◽  
Qingjie Wang ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Transcription Factor ◽  
Heart Disease ◽  
Subcellular Localization ◽  
Protein Expression ◽  
Heart Development ◽  
Congenital Heart ◽  
Target Genes ◽  
Physical Interaction ◽  
Healthy Controls

Abstract Background: The protein Kruppel-like factor 13 (KLF13) is a member of the KLF family and has been identified as a cardiac transcription factor that is involved in heart development. However, the relationship between KLF13 variants and CHDs in humans remains largely unknown. The present study aimed to screen the KLF13 variants in CHD patients and genetically analyze the functions of these variants. Methods: KLF13 variants were sequenced in a cohort of 309 CHD patients and population-matched healthy controls (n = 200) using targeted sequencing. To investigate the effect of variants on the functional properties of the KLF13 protein, the expression and subcellular localization of the protein, as well as the transcriptional activities of downstream genes and physical interactions with other transcription factors, were assessed. Results: Two heterozygous variants, c.487C>T (P163S) and c.467G>A (S156N), were identified in two out of 309 CHD patients with tricuspid valve atresia and transposition of the great arteries, respectively. No variants were found among healthy controls. The variant c.467G>A (S156N) had increased protein expression and enhanced functionality compared with the wild type, without affecting the subcellular localization. The other variant, c.487C>T (P163S), did not show any abnormalities in protein expression or subcellular localization; however, it inhibited the transcriptional activities of downstream target genes and physically interacted with TBX5, another cardiac transcription factor. Conclusion: Our results show that the S156N and P163S variants may affect the transcriptional function of KLF13 and physical interaction with TBX5. These results identified KLF13 as a potential genetic risk factor for congenital heart disease.

scholarly journals Identification and analysis of KLF13 variants in patients with congenital heart disease

2019 ◽  
Author(s):  
Wenjuan Li ◽  
Baolei Li ◽  
Tingting Li ◽  
Ergeng Zhang ◽  
Qingjie Wang ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Transcription Factor ◽  
Heart Disease ◽  
Subcellular Localization ◽  
Protein Expression ◽  
Heart Development ◽  
Congenital Heart ◽  
Target Genes ◽  
Healthy Controls ◽  
Downstream Target

Abstract Background: The protein Kruppel-like factor 13 (KLF13) is a member of the KLF family that has been identified as a novel cardiac transcription factor which is involved in heart development. However, the relationship between KLF13 variants and CHDs in humans remains largely unknown. The present study aimed to screen the KLF13 variants in CHDs patients and genetically analyze the function of these variants. Methods: KLF13 variants were sequenced in a cohort of 309 CHD patients and population-matched healthy controls (n = 200) using targeted sequencing. To investigate the effect of variants on the functional ability of the KLF13 protein, the expressions and subcellular localization of protein, as well as the transcriptional activities of downstream genes and physically interacted with other transcription factor were assessed. Results: Two novel heterozygous variants, c.487C>T (P163S) and c.467G>A (S156N), were identified in two out of 309 CHDs patients with Tricuspid-valve atresia and transposition of the great arteries, respectively. No variants were found among healthy controls. The variant c.467G>A (S156N) increased protein expression and enhanced functionality compared with that of wild-type, without affecting the subcellular localization. The other variant, c.487C>T (P163S), did not show any abnormalities in protein expression and subcellular localization, however it eliminated the transcriptional activities of downstream target genes and physically interacted with TBX5, another cardiac transcription factor. Conclusion: Our results show that the S156N and P163S variants contributed to CHD etiology. Additionally, our findings suggest that KLF13 may be a potential gene contributing to congenital heart disease.

scholarly journals Identification and analysis of KLF13 variants in patients with congenital heart disease

2020 ◽  
Author(s):  
Wenjuan Li ◽  
Baolei Li ◽  
Tingting Li ◽  
Ergeng Zhang ◽  
Qingjie Wang ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Transcription Factor ◽  
Heart Disease ◽  
Subcellular Localization ◽  
Protein Expression ◽  
Heart Development ◽  
Congenital Heart ◽  
Target Genes ◽  
Physical Interaction ◽  
Healthy Controls

Abstract Background: The protein Kruppel-like factor 13 (KLF13) is a member of the KLF family that has been identified as a cardiac transcription factor which is involved in heart development. However, the relationship between KLF13 variants and CHDs in humans remains largely unknown. The present study aimed to screen the KLF13 variants in CHDs patients and genetically analyze the function of these variants. Methods: KLF13 variants were sequenced in a cohort of 309 CHD patients and population-matched healthy controls (n = 200) using targeted sequencing. To investigate the effect of variants on the functional ability of the KLF13 protein, the expressions and subcellular localization of protein, as well as the transcriptional activities of downstream genes and physically interacted with other transcription factor were assessed. Results: Two heterozygous variants, c.487C>T (P163S) and c.467G>A (S156N), were identified in two out of 309 CHDs patients with Tricuspid-valve atresia and transposition of the great arteries, respectively. No variants were found among healthy controls. The variant c.467G>A (S156N) increased protein expression and enhanced functionality compared with that of wild-type, without affecting the subcellular localization. The other variant, c.487C>T (P163S), did not show any abnormalities in protein expression and subcellular localization, however it eliminated the transcriptional activities of downstream target genes and physically interacted with TBX5, another cardiac transcription factor. Conclusion: Our results show that the S156N and P163S variants may affect the transcriptional function of KLF13 and physical interaction with TBX5, These results identified KLF13 maybe as a potential genetic risk factor for congenital heart disease.

scholarly journals Identification of Novel Single-Nucleotide Variants With Potential of Mediating Malfunction of MicroRNA in Congenital Heart Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Wangkai Liu ◽  
Liangping Cheng ◽  
Ken Chen ◽  
Jialing Wu ◽  
Rui Peng ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Target Genes ◽  
Heart Defects ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Downstream Target ◽  
Gene Dysregulation ◽  
Great Vessels

Congenital heart defects (CHDs) represent the most common human birth defects. Our previous study indicates that the malfunction of microRNAs (miRNAs) in cardiac neural crest cells (NCCs), which contribute to the development of the heart and the connected great vessels, is likely linked to the pathogenesis of human CHDs. In this study, we attempt to further search for causative single-nucleotide variants (SNVs) from CHD patients that mediate the mis-regulating of miRNAs on their downstream target genes in the pathogenesis of CHDs. As a result, a total of 2,925 3′UTR SNVs were detected from a CHD cohort. In parallel, we profiled the expression of miRNAs in cardiac NCCs and found 201 expressed miRNAs. A combined analysis with these data further identified three 3′UTR SNVs, including NFATC1 c.*654C>T, FGFRL1 c.*414C>T, and CTNNB1 c.*729_*730insT, which result in the malfunction of miRNA-mediated gene regulation. The dysregulations were further validated experimentally. Therefore, our study indicates that miRNA-mediated gene dysregulation in cardiac NCCs could be an important etiology of congenital heart disease, which could lead to a new direction of diagnostic and therapeutic investigation on congenital heart disease.

scholarly journals Exome Sequencing and Congenital Heart Disease in Sub-Saharan Africa

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Ekanem N. Ekure ◽  
Adebowale Adeyemo ◽  
Hanhan Liu ◽  
Ogochukwu Sokunbi ◽  
Nnenna Kalu ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Exome Sequencing ◽  
Congenital Heart ◽  
De Novo ◽  
Sub Saharan Africa ◽  
Disease Genes ◽  
Loss Of Function ◽  
Unique Identifier ◽  
Sub Saharan

Background: Congenital heart disease (CHD) is the most common birth defect and affects roughly 1% of the global population. There have been many large CHD sequencing projects in developing countries but none in sub-Saharan Africa. In this exome sequencing study, we recruited families from Lagos, Nigeria, affected by structural heart disease. Methods: Ninety-eight participants with CHD and an average age of 3.6 years were recruited from Lagos, Nigeria. Exome sequencing was performed on probands and parents when available. For genes of high interest, we conducted functional studies in Drosophila using a cardiac-specific RNA interference–based gene silencing system. Results: The 3 most common CHDs were tetralogy of Fallot (20%), isolated ventricular septal defect (14%), and transposition of the great arteries (8%). Ten percent of the cohort had pathogenic or likely pathogenic variants in genes known to cause CHD. In 64 complete trios, we found 34 de novo variants that were not present in the African population in the Genome Aggregation Database (v3). Nineteen loss of function variants were identified using the genome-wide distribution of selection effects for heterozygous protein-truncating variants (s het ). Nine genes caused a significant mortality when silenced in the Drosophila heart, including 4 novel disease genes not previously associated with CHD ( UBB, EIF4G3, SREBF1 , and METTL23 ). Conclusions: This study identifies novel candidate genes and variants for CHD and facilitates comparisons with previous CHD sequencing studies in predominantly European cohorts. The study represents an important first step in genomic studies of CHD in understudied populations. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01952171.

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