scholarly journals Navigating the non-coding genome in heart development and Congenital Heart Disease

2019 ◽  
Vol 107 ◽  
pp. 11-23 ◽  
Author(s):  
Gulrez Chahal ◽  
Sonika Tyagi ◽  
Mirana Ramialison
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Heart Development ◽  
Congenital Heart

scholarly journals A Non-coding HES1 Variant Predisposes Children to Congenital Heart Disease in Chinese Population

2021 ◽  
Vol 9 ◽  
Author(s):  
Yangliu Song ◽  
Weicheng Chen ◽  
Zitong Huang ◽  
Guixiang Tian ◽  
Mengru Li ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Association Analysis ◽  
Heart Development ◽  
Congenital Heart ◽  
Genetic Model ◽  
Gain Of Function ◽  
Coding Sequence ◽  
Homozygous Variant ◽  
Increased Risk

Background: As a key component in the NOTCH signaling pathway, HES1 plays an important role in vertebrate heart development. Variants in the HES1 coding sequence are known to be associated with congenital heart disease (CHD). However, little is known about HES1 non-coding sequence variants and their association with the risk of developing CHD.Method and Results: We initially analyzed the non-coding sequence of the HES1 gene in 12 unrelated CHD families by direct sequencing and identified a previously unreported promoter region variant (NM_005524.4: c.−1279−1278 insAC, rs148941464) in the HES1 gene in four CHD families. The homozygous variant in patients was inherited from carrier parents with normal phenotypes, indicating a likely recessive genetic model. Given that the HES1 gene is predicted to be likely to exhibit haploinsufficiency (%HI: 11.44), we hypothesized that the HES1 homozygous variant is a genetic risk factor underlying CHD. We then carried out sequencing of this HES1 variant in 629 sporadic non-syndromic CHD cases and 696 healthy controls and performed association analysis. Interestingly, we observed a significant association of the homozygous HES1 promoter variant with CHD (18.92% of cases vs. 9.91% of controls; OR: 2.291, 95% CI: 1.637-3.207, p = 9.72 × 10−7). No significant association with CHD was observed for the HES1 promoter heterozygous variant (p > 0.05). However, association analysis tests of the HES1 homozygous variant with each subtype of CHD revealed that this homozygous variant was strongly associated with transposition of the great arteries (TGA) (OR: 3.726, 95% CI: 1.745-7.956, p = 0.0003). Moreover, the prevalence of HES1 homozygous variants in CHD patients with TGA (27.66%) was significantly higher than that in patients with other CHD subtypes or controls. Similar results were observed in a replication group of TGA (n = 64). Functional studies demonstrated that the homozygous variant in the HES1 promoter can disrupt its ability to bind RXRA, an inhibitory transcription factor, which results in abnormally high expression of the HES1 gene, indicating that this variant harbors gain-of-function effects.Conclusions: Our findings reveal that the non-coding homozygous variant in the HES1 promoter has a gain-of-function effect and is associated with an increased risk of CHD development, especially the severe TGA subtype.

scholarly journals Missense Mutation in the Transcription Factor NKX2–5: A Novel Molecular Event in the Pathogenesis of Thyroid Dysgenesis

2006 ◽  
Vol 91 (4) ◽  
pp. 1428-1433 ◽  
Author(s):  
Monica Dentice ◽  
Viviana Cordeddu ◽  
Annamaria Rosica ◽  
Alfonso Massimiliano Ferrara ◽  
Libero Santarpia ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Transcription Factor ◽  
Heart Disease ◽  
Heart Development ◽  
Congenital Heart ◽  
Functional Characterization ◽  
Dominant Negative Effect ◽  
Thyroid Dysgenesis ◽  
Thyroid Development

Context: Congenital hypothyroidism (CH) is a common endocrine disorder with an incidence of 1:3000–4000 at birth. In 80–85% of cases, CH is caused by defects in thyroid organogenesis, resulting in absent, ectopically located, and/or severely reduced gland [thyroid dysgenesis (TD)]. Mutations in genes controlling thyroid development have demonstrated that in a few cases, TD is a Mendelian trait. However, accumulating evidence supports the view that the genetics of TD are complex, possibly with a polygenic/multifactorial basis. A higher prevalence of congenital heart disease has been documented in children with CH than in the general population. Such an association suggests a possible pathogenic role of genes involved in both heart and thyroid development. NKX2–5 encodes a homeodomain-containing transcription factor with a major role in heart development, and mutations affecting this gene have been reported in individuals with congenital heart disease. Objective: In the present work we investigated the possible involvement of NKX2–5 mutations in TD. Results: Our results indicate that Nkx2–5−/− embryos exhibit thyroid bud hypoplasia, providing evidence that NKX2–5 plays a role in thyroid organogenesis and that NKX2–5 mutations contribute to TD. NKX2–5 mutational screening in 241 patients with TD allowed the identification of three heterozygous missense changes (R25C, A119S, and R161P) in four patients with TD. Functional characterization of the three mutations demonstrated reduced DNA binding and/or transactivation properties, with a dominant-negative effect on wild-type NKX2–5. Conclusion: Our results suggest a previously unknown role of NKX2–5 in the pathogenesis of TD.

Molecular insight into heart development and congenital heart disease: An update review from the Arab countries

2015 ◽  
Vol 25 (4) ◽  
pp. 291-301 ◽  
Author(s):  
Elhadi H. Aburawi ◽  
Hanan E. Aburawi ◽  
Keith M. Bagnall ◽  
Zahurul A. Bhuiyan
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Heart Development ◽  
Congenital Heart ◽  
Arab Countries ◽  
Insight Into

scholarly journals Genetics of Congenital Heart Disease

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 879 ◽  
Author(s):  
Kylia Williams ◽  
Jason Carson ◽  
Cecilia Lo
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Cell Signaling ◽  
Heart Development ◽  
Congenital Heart ◽  
Genetic Etiology ◽  
Genes Encoding ◽  
Related Proteins ◽  
Improve Patient ◽  
Cell Signaling Pathways

Congenital heart disease (CHD) is one of the most common birth defects. Studies in animal models and humans have indicated a genetic etiology for CHD. About 400 genes have been implicated in CHD, encompassing transcription factors, cell signaling molecules, and structural proteins that are important for heart development. Recent studies have shown genes encoding chromatin modifiers, cilia related proteins, and cilia-transduced cell signaling pathways play important roles in CHD pathogenesis. Elucidating the genetic etiology of CHD will help improve diagnosis and the development of new therapies to improve patient outcomes.

Mitochondrial mutations in patients with congenital heart defects by next generation sequencing technology

2014 ◽  
Vol 25 (4) ◽  
pp. 705-711 ◽  
Author(s):  
Neslihan Abaci ◽  
Muzaffer Arıkan ◽  
Türkan Tansel ◽  
Nazlı Sahin ◽  
Aris Cakiris ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Next Generation Sequencing ◽  
Nucleic Acid ◽  
Heart Development ◽  
Congenital Heart ◽  
Heart Defects ◽  
Next Generation ◽  
Oxidative Energy Metabolism ◽  
Generation Sequencing

AbstractIt has been shown that mitochondrial deoxyribo nucleic acid mutations may play an important role in the development of cardiomyopathy, and various types of cardiomyopathy can be attributed to disturbed mitochondrial oxidative energy metabolism. Several studies have described many mutations in mitochondrial genes encoding for subunits of respiratory chain complexes. Thus, recent studies confirm that pathologic mitochondrial deoxyribo nucleic acid mutations are a major reason of diseases and determining them by next-generation sequencing will improve our understanding of dysregulation of heart development. To analyse mitochondrial deoxyribo nucleic acid mutations, the entire mitochondrial deoxyribo nucleic acid was amplified in two overlapping polymerase chain reaction fragments from the cardiac tissue of the 22 patients with congenital heart disease, undergoing cardiac surgery. Mitochondrial deoxyribo nucleic acid was deep sequenced by next-generation sequencing. A total of 13 novel mitochondrial deoxyribo nucleic acid mutations were identified in nine patients. Of the patients, three have novel mutations together with reported cardiomyopathy mutations. In all, 65 mutations were found, and 13 of them were unreported. This study represents the most comprehensive mitochondrial deoxyribo nucleic acid mutational analysis in patients with 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 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.

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