Biochemical analyses of eight NKX2.5 homeodomain missense mutations causing atrioventricular block and cardiac anomalies

Kasahara, Hideko; Benson, D. Woodrow

doi:10.1016/j.cardiores.2004.06.004

Cited by 101 publications

(92 citation statements)

References 41 publications

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“…Our results are supported by the finding of other NKX2-5 mutations predisposing to congenital CHD by impairing or reducing cardiac transcription factor NKX2-5 (Kasahara et al, 2000;Kasahara and Benson, 2004). To date, more than 40 mutations in NKX2-5 have been described, of which more than 30 mutations have been observed in patients with atrial septal defect, showing that although NKX2-5 mutations are involved in a long list of cardiac malformations, the most frequent phenotype resulted is atrial septal defect (Stallmeyer et al, 2010).…”

Section: Discussionsupporting

confidence: 86%

Novel NKX2-5 mutations responsible for congenital heart disease

Wang

Xy²,

Yq³

2011

Genet. Mol. Res.

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ABSTRACT. Congenital heart disease (CHD) is the most common birth defect and is the leading cause of infant morbidity and mortality resulting from birth defects. Increasing evidence demonstrates that genetic variation in the NKX2-5 gene, which encodes a homeobox-containing transcription factor crucial to cardiogenesis, is an important molecular determinant for CHD. Nevertheless, the genetic components underlying CHD remain largely unknown. We screened NKX2-5 for potential molecular defects in patients with CHD. The entire coding region of NKX2-5 was initially sequenced in a cohort of 268 unrelated patients with CHD. The relatives of the patients carrying identified mutations and 200 unrelated control individuals were subsequently genotyped. Three novel heterozygous missense NKX2-5 mutations, p.Q22K, p.R36S, and p.E54K, were identified in three families with autosomal dominantly inherited atrial septal defect, ventricular septal defect, and tetralogy of Fallot, respectively. These mutations, absent in 200 control individuals, appear to be highly conserved evolutionarily and co-segregated with CHD in the families, with complete penetrance. These findings expand the spectrum of mutations in NKX2-5 associated with CHD and provide new insight into the molecular etiology involved in the pathogenesis of CHD, which signifies potential implications for genetic diagnosis and gene-specific therapy for this common disease in newborns.

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Section: Discussionsupporting

confidence: 86%

Novel NKX2-5 mutations responsible for congenital heart disease

Wang

Xy²,

Yq³

2011

Genet. Mol. Res.

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“…The identification that GATA4 mutations associated with CHD have hypomorphic transactivation ability not always explained by DNA binding deficits is consistent with the dosage sensitivity of GATA4. These findings are different from those reported for NKX2-5 mutations which usually exhibit decreased transactivation ability and associated reduced DNA binding affinity [Kasahara and Benson, 2004]. In summary, the results of in vitro biochemical studies are consistent with reports of human patients who have similar types of CHD and harbor deletions of chromosome 8p that lead to haploinsufficiency of GATA4 [Pehlivan et al, 1999].…”

Section: Discussionsupporting

confidence: 68%

“…Subsequently, other investigators have reported additional GATA4 mutations, S52F, E216D and E358del, in individuals with non-syndromic CHD [Okubo et al, 2004;Hirayama-Yamada et al, 2005;Sarkozy et al, 2005;Nemer et al, 2006]. We hypothesize that mutations in GATA4 are present in diverse types of non-syndromic CHD similar to NKX2.5, and that these mutations might result in alterations of Gata4 function in biochemical assays thereby accounting for genotype-phenotype differences [Benson et al, 1999;Kasahara et al, 2000;Goldmuntz et al, 2001;Kasahara and Benson, 2004]. To determine the frequency of GATA4 mutations in patients with non-syndromic CHD, we studied 157 individuals with sporadic and familial cases of CHD and tested novel and previously unstudied GATA4 mutations in biochemical assays to identify in vitro functional deficits.…”

Section: Introductionmentioning

confidence: 73%

Screening and biochemical analysis of GATA4 sequence variations identified in patients with congenital heart disease

Schluterman

Krysiak

Kathiriya

et al. 2007

American J of Med Genetics Pt A

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Few known monogenic causes of non-syndromic congenital heart disease (CHD) have been identified. Mutations in NKX2.5 were initially implicated in familial cases of cardiac septal defects and subsequently, functionally significant NKX2.5 mutations were found in diverse forms of non-syndromic CHD. Similarly, mutations in GATA4, which encodes a cardiac transcription factor, were first identified in familial cases of cardiac septal defects. We hypothesize that individuals with non-syndromic CHD may harbor GATA4 mutations and that these mutations alter the biochemical properties of the protein. The coding region encompassing the six exons of GATA4 was screened in a study population of 157 patients with CHD. We identified several sequence variations in GATA4. We tested these novel sequence variations that altered evolutionarily conserved amino acids and other previously reported GATA4 mutations in various biochemical assays. The novel sequence variations had no biochemical deficits while a previously reported, but unstudied, missense mutation in GATA4 (S52F) functioned as a hypomorph in transactivation assays. We did not identify any novel GATA4 mutations in our patient population with non-syndromic CHD. Consistent with previous findings, GATA4 mutations that result in deficits in transactivation ability are consistently associated with CHD suggesting that normal transactivation properties of GATA4 are required for proper cardiac development.

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“…Although Thr 41 is not involved in direct hydrogen bonding with the NKX3.1 DNA recognition sequence, it is likely to affect helix III structure and both DNA and protein interactions. The homologous Thr 41 in the human tinman homologue NKX2.5 has been mutated to methionine in a family with hereditary atrial septal defect and atrioventricular block (49). The NKX2.5 (T178M), homeodomain T41M, mutation causes marked reduction in DNA-binding affinity of NKX2.5 but does not affect complex formation either with wild-type NKX2.5 or with GATA4.…”

Section: Discussionmentioning

confidence: 99%

Germ-Line Mutation of NKX3.1 Cosegregates with Hereditary Prostate Cancer and Alters the Homeodomain Structure and Function

Zheng

Chang

et al. 2006

Cancer Research

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NKX3.1, a gene mapped to 8p21, is a member of the NK class of homeodomain proteins and is expressed primarily in the prostate. NKX3.1 exerts a growth-suppressive and differentiating effect on prostate epithelial cells. Because of its known functions and its location within a chromosomal region where evidence for prostate cancer linkage and somatic loss of heterozygosity is found, we hypothesize that sequence variants in the NKX3.1 gene increase prostate cancer risk. To address this, we first resequenced the NKX3.1 gene in 159 probands of hereditary prostate cancer families recruited at Johns Hopkins Hospital; each family has at least three first-degree relatives affected with prostate cancer. Twenty-one germ-line variants were identified in this analysis, including one previously described common nonsynonymous change (R52C), two novel rare nonsynonymous changes (A17T and T164A), and a novel common 18-bp deletion in the promoter. Overall, the germline variants were significantly linked to prostate cancer, with a peak heterogeneity logarithm of odds of 2.04 (P = 0.002) at the NKX3.1 gene. The rare nonsynonymous change, T164A, located in the homeobox domain of the gene, segregated with prostate cancer in a family with three affected brothers and one unaffected brother. Importantly, nuclear magnetic resonance solution structure analysis and circular dichroism studies showed this specific mutation to affect the stability of the homeodomain of the NKX3.1 protein and decreased binding to its cognate DNA recognition sequence. These results suggest that germ-line sequence variants in NKX3

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Biochemical analyses of eight NKX2.5 homeodomain missense mutations causing atrioventricular block and cardiac anomalies

Cited by 101 publications

References 41 publications

Novel NKX2-5 mutations responsible for congenital heart disease

Novel NKX2-5 mutations responsible for congenital heart disease

Screening and biochemical analysis of GATA4 sequence variations identified in patients with congenital heart disease

Germ-Line Mutation of NKX3.1 Cosegregates with Hereditary Prostate Cancer and Alters the Homeodomain Structure and Function

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