Bonachea Elizabeth M, Chang Sheng-Wei, Zender Gloria, LaHaye Stephanie, Fitzgerald-Butt Sara, McBride Kim L, Garg Vidu
Department of Pediatrics, The Ohio State University, Columbus, Ohio.
1] Center for Cardiovascular and Pulmonary Research, Nationwide Children's Hospital, Columbus, Ohio [2] The Heart Center, Nationwide Children's Hospital, Columbus, Ohio.
Pediatr Res. 2014 Aug;76(2):211-6. doi: 10.1038/pr.2014.67. Epub 2014 May 5.
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.
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.
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.
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.
二叶式主动脉瓣（BAV）是最常见的先天性心脏病（CHD）类型，且有推测其存在遗传病因。BAV按瓣叶融合情况分类，左右（R-L）瓣叶融合与其他CHD相关，右-无冠状动脉瓣叶（R-NC）融合与主动脉瓣功能障碍相关。编码心脏转录因子的小鼠Gata5缺失会导致部分显性的R-NC型BAV，我们推测GATA5突变与人类R-NC型BAV相关。
对78例BAV患者队列（50例孤立性BAV和28例合并主动脉缩窄）进行桑格测序分析以鉴定GATA5序列变异。进行生化分析以鉴定所鉴定序列变异的功能缺陷。
我们鉴定出两个罕见的杂合非同义变异，即p.Gln3Arg和p.Leu233Pro，频率为2.6%（2/78）。两个携带非同义变异的个体均患有BAV和主动脉缩窄，一个为R-L亚型，一个为R-NC亚型。在非同义变异中，只有p.Gln3Arg在体外表现出转录活性降低。
GATA5中的罕见序列变异与人类BAV相关。我们的研究结果提示在合并的CHD方面存在基因型-表型相关性，但在瓣叶融合方面不存在。
