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.

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 The microbiome’s relationship with congenital heart disease: more than a gut feeling

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Dan Feng ◽  
Jason T. Christensen ◽  
Anji T. Yetman ◽  
Merry L. Lindsey ◽  
Amar B. Singh ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Patient Population ◽  
Congenital Heart ◽  
Basic Research ◽  
Intestinal Epithelial ◽  
Barrier Dysfunction ◽  
Intestinal Dysbiosis ◽  
Epithelial Barrier Dysfunction

AbstractPatients with congenital heart disease (CHD) are at risk for developing intestinal dysbiosis and intestinal epithelial barrier dysfunction due to abnormal gut perfusion or hypoxemia in the context of low cardiac output or cyanosis. Intestinal dysbiosis may contribute to systemic inflammation thereby worsening clinical outcomes in this patient population. Despite significant advances in the management and survival of patients with CHD, morbidity remains significant and questions have arisen as to the role of the microbiome in the inflammatory process. Intestinal dysbiosis and barrier dysfunction experienced in this patient population are increasingly implicated in critical illness. This review highlights possible CHD-microbiome interactions, illustrates underlying signaling mechanisms, and discusses future directions and therapeutic translation of the basic research.

The role of EEG recordings in children undergoing cardiac surgery for congenital heart disease

2017 ◽  
Vol 167 (11-12) ◽  
pp. 251-255
Author(s):  
Sascha Meyer ◽  
Martin Poryo ◽  
Mohammed Shatat ◽  
Ludwig Gortner ◽  
Hashim Abdul-Khaliq
Keyword(s):  
Congenital Heart Disease ◽  
Cardiac Surgery ◽  
Heart Disease ◽  
Congenital Heart ◽  
Eeg Recordings

Extracorporeal membrane oxygenation and cyanotic congenital heart disease

1992 ◽  
Vol 2 (4) ◽  
pp. 359-360 ◽  
Author(s):  
Gale A. Pearson ◽  
Richard K. Firmin ◽  
Ranjit Leanage
Keyword(s):  
Congenital Heart Disease ◽  
United Kingdom ◽  
Heart Disease ◽  
Extracorporeal Membrane Oxygenation ◽  
Congenital Heart ◽  
Cyanotic Congenital Heart Disease ◽  
Membrane Oxygenation ◽  
The United Kingdom

AbstractWorldwide figures suggest that two percent of appropriate referrals for neonatal extracorporeal membrane oxygenation turn out to have previously covert congenital heart disease. This is despite the fact that expert cardiological evaluation is routine prior to cannulation. The experience in the United Kingdom includes such a case which is reported here. The implications for the role of pediatric cardiologists in such a service are considered.

ABNORMAL CAPILLARY MORPHOLOGY IN CONGENITAL HEART DISEASE

PEDIATRICS ◽  
1966 ◽  
Vol 37 (2) ◽  
pp. 316-322
Author(s):  
Stella B. Kontras ◽  
JoAnn G. Bodenbender
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
Septal Defect ◽  
Chronic Hypoxia ◽  
Normal Children ◽  
Vascular Abnormalities ◽  
Definitive Surgery ◽  
Vascular Compartment

Capillary morphology has been studied in 111 normal children. In 98% of these cases, straight hairpin forms make up over 80% of the capillaries examined. Thirty children with congenital heart disease showed 80% abnormal capillary patterns consisting of dilated, tortuous, and branched loops. These were most marked in cyanotic tetralogy of Fallot and ventricular septal defect with pulmonary hypertension. These cases also were associated with microscopic hemorrhages, increased capillary fragility and actual postoperative hemorrhagic complications. Definitive surgery in two cases, though improving the patient, did not result in changes in the abnormal capillary patterns. It is suggested that the role of the capillary structure in rheology of blood in the microvasculature has largely been ignored and that abnormalities in this vascular compartment may affect perfusion of tissues. The association of abnormalities in coagulation studies, hemorrhage, and thrombosis with congenital heart disease may in part be related to the morphologic vascular abnormalities. The abnormal capillary findings may be due to maturational arrest or dysmaturity of this portion of the cardiovascular system or may be the result of chronic hypoxia.

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