Molecular analysis of PRKAG2, LAMP2, and NKX2‐5 genes in a cohort of 125 patients with accessory atrioventricular connection

Esposito, Giulia; Grutter, Giorgia; Drago, Fabrizio; Costa, Mauro W.; Santis, Antonella De; Bosco, Giovanna; Marino, Bruno; Bellacchio, Emanuele; Lepri, Francesca; Harvey, Richard P.; Sárközy, Anna; Dallapiccola, Bruno

doi:10.1002/ajmg.a.32907

Cited by 17 publications

(17 citation statements)

References 26 publications

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“…This gave a detection frequency of 0.74%, lower than those reported previously (1.4-4.8%) (Elliott et al 2003;Esposito et al 2009;McElhinney et al 2003). The parents of this patient were non-smokers.…”

Section: Phenotypes Of Nkx25 Mutationscontrasting

confidence: 52%

“…A number of missense and nonsense mutations in NKX2.5 have been found in families with inherited autosomaldominant ASD and atrioventricular conduction block (Table 6; Akcaboy et al 2008;Benson et al 1999;Ding et al 2009;Elliott et al 2003;Esposito et al 2009;GioliPereira et al 2010;Goldmuntz et al 2001;GutierrezRoelens et al 2002;Hobbs et al 2005;Hosoda et al 1999;Ikeda et al 2002;Liu et al 2009a, b;McElhinney et al 2003;Schott et al 1998;Stallmeyer et al 2010;Watanabe et al 2002;Zhang et al 2009a, b). Other congenital heart abnormalities have been observed at low penetrance in these families, including VSD, Ebstein's anomaly, TOF, subvalvular aortic stenosis, and tricuspid valve abnormality.…”

Section: Discussionmentioning

confidence: 99%

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Mutations of the GATA4 and NKX2.5 genes in Chinese pediatric patients with non-familial congenital heart disease

et al. 2010

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A number of mutations in GATA4 and NKX2.5 have been identified to be causative for a subset of familial congenital heart defects (CHDs) and a small number of sporadic CHDs. In this study, we evaluated common GATA4 and NKX2.5 mutations in 135 Chinese pediatric patients with non-familial congenital heart defects. Two novel mutations in the coding region of GATA4 were identified, namely, 487C >T (Pro163Ser) in exon 1 in a child with tetralogy of Fallot and 1220C >A (Pro407Gln) in exon 6 in a pediatric patient with outlet membranous ventricular septal defect. We also found 848C >A (Pro283Gln) in exon 2 of the NKX2.5 gene in a pediatric patient with ventricular septal defect, patent ductus arteriosus and aortic isthmus stenosis. None of the mutations was detected in healthy control subjects (n = 114). This study suggests that GATA4 and NKX2.5 missense mutations may be associated with congenital heart defects in pediatric Chinese patients. Further clinical studies with large samples are warranted.

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Section: Phenotypes Of Nkx25 Mutationscontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Mutations of the GATA4 and NKX2.5 genes in Chinese pediatric patients with non-familial congenital heart disease

et al. 2010

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“…Only 5 of 41 (12%) have been reported more than once in unrelated individuals, with c.73C>T (p.R25C) being frequently detected. However, p.R25C was also found in unaffected relatives and controls; hence, its pathogenicity remains unclear [Akcaboy et al, 2008; Esposito et al, 2009; Gioli‐Pereira et al, 2010; Goldmuntz et al, 2001].…”

Section: An Update Of Nkx2–5 Germline Mutationsmentioning

confidence: 99%

“… a a For the functional studies, see Kasahara et al [2000], Kasahara and Benson [2004], Zhu et al [2000], Monzen et al [2002], Inga et al [2005], and Esposito et al [2009]. …”

Section: Functional Significance Of Nkx2–5 Mutationsmentioning

confidence: 99%

“…Table S3). Essentially, NKX2–5 mutations affecting the homeodomain resulted in reduced or loss of DNA binding, transactivation activities, and protein–protein interactions, particularly with GATA4 and TBX5 [Esposito et al, 2009; Inga et al, 2005; Kasahara et al, 2000; Kasahara and Benson, 2004; Monzen et al, 2002; Zhu et al, 2000].…”

Section: Functional Significance Of Nkx2–5 Mutationsmentioning

confidence: 99%

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NKX2-5: an update on this hypermutable homeodomain protein and its role in human congenital heart disease (CHD)

2010

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Congenital heart disease (CHD) is among the most prevalent and fatal of all birth defects. Deciphering its causes, however, is complicated, as many patients affected by CHD have no family history of the disease. There is also widespread heterogeneity of cardiac malformations within affected individuals. Nonetheless, there have been tremendous efforts toward a better understanding of the molecular and cellular events leading to CHD. Notably, certain cardiac-specific transcription factors have been implicated in mammalian heart development and disruption of their activity has been demonstrated in CHD. The homeodomain transcription factor NKX2-5 is an important member of this group. Indeed, more than 40 heterozygous NKX2-5 germline mutations have been observed in individuals with CHD, and these are spread along the coding region, with many shown to impact protein function. Thus, NKX2-5 appears to be hypermutable, yet the overall detection frequency in sporadic CHD is about 2% and NKX2-5 mutations are one-time detections with single-positives or private to families. Furthermore, there is lack of genotype-phenotype correlation, in which the same cardiac malformations have been exhibited in different NKX2-5 mutations or the same NKX2-5 mutation associated with diverse malformations. Here, we summarize published NKX2-5 germline mutations and explore different avenues in disease pathogenesis to support the notion of a multifactorial cause of CHD where possibly several genes and associated pathways are involved.

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An update on genetic variants of theNKX2‐5

et al. 2020

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NKX2‐5 is a homeodomain transcription factor that plays a crucial role in heart development. It is the first gene where a single genetic variant (GV) was found to be associated with congenital heart diseases in humans. In this study, we carried out a comprehensive survey of NKX2‐5 GVs to build a unified, curated, and updated compilation of all available GVs. We retrieved a total of 1,380 unique GVs. From these, 970 had information on their frequency in the general population and 143 have been linked to pathogenic phenotypes in humans. In vitro effect was ascertained for 38 GVs. The homeodomain had the biggest cluster of pathogenic variants in the protein: 49 GVs in 60 residues, 23 in its third α‐helix, where 11 missense variants may affect protein–DNA interaction or the hydrophobic core. We also pinpointed the likely location of pathogenic GVs in four linear motifs. These analyses allowed us to assign a putative explanation for the effect of 90 GVs. This study pointed to reliable pathogenicity for GVs in helix 3 of the homeodomain and may broaden the scope of functional and structural studies that can be done to better understand the effect of GVs in NKX2‐5 function.

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Molecular analysis of PRKAG2, LAMP2, and NKX2‐5 genes in a cohort of 125 patients with accessory atrioventricular connection

Cited by 17 publications

References 26 publications

Mutations of the GATA4 and NKX2.5 genes in Chinese pediatric patients with non-familial congenital heart disease

Mutations of the GATA4 and NKX2.5 genes in Chinese pediatric patients with non-familial congenital heart disease

NKX2-5: an update on this hypermutable homeodomain protein and its role in human congenital heart disease (CHD)

An update on genetic variants of theNKX2‐5

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