Rare GATA5 sequence variants identified in individuals with bicuspid aortic valve.

Abstract:

BACKGROUND:Bicuspid aortic valve (BAV) is the most common type of congenital heart disease (CHD) and has a proposed genetic etiology. BAV is categorized by cusp fusion, with right-left (R-L) cusp fusion being associated with additional CHD, and right-noncoronary cusp (R-NC) fusion being associated with aortic valve dysfunction. Loss of murine Gata5, which encodes a cardiac transcription factor, results in a partially penetrant R-NC BAV, and we hypothesize that mutations in GATA5 are associated with R-NC BAV in humans. METHODS:A cohort of 78 BAV patients (50 with isolated BAV and 28 with associated aortic coarctation) was analyzed using Sanger sequencing to identify GATA5 sequence variants. Biochemical assays were performed to identify functional deficits of identified sequence variants. RESULTS:We identified two rare heterozygous nonsynonymous variants, p.Gln3Arg and p.Leu233Pro, for a frequency of 2.6% (2/78). Both individuals with nonsynonymous variants had BAV and aortic coarctation, one R-L and one R-NC subtype. Of the nonsynonymous variants, only p.Gln3Arg demonstrated decreased transcriptional activity in vitro. CONCLUSION:Rare sequence variants in GATA5 are associated with human BAV. Our findings suggest a genotype-phenotype correlation in regards to associated CHD but not cusp fusion.

journal_name

Pediatr Res

journal_title

Pediatric research

authors

Bonachea EM,Chang SW,Zender G,LaHaye S,Fitzgerald-Butt S,McBride KL,Garg V

doi

10.1038/pr.2014.67

subject

Has Abstract

pub_date

2014-08-01 00:00:00

pages

211-6

issue

2

eissn

0031-3998

issn

1530-0447

pii

pr201467

journal_volume

76

pub_type

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