Compound heterozygous GATA5 mutations in a girl with hydrops fetalis, congenital heart defects and genital anomalies

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• 作者：Maja Hempel ; Teresa Casar Tena ; Thilo Diehl ; Martina S. Burczyk…
• 刊名：Human Genetics
• 出版年：2017
• 出版时间：March 2017
• 年：2017
• 卷：136
• 期：3
• 页码：339-346
• 全文大小：
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Human Genetics; Molecular Medicine; Gene Function; Metabolic Diseases;
• 出版者：Springer Berlin Heidelberg
• ISSN：1432-1203
• 卷排序：136

文摘

GATA5 belongs to the GATA family of transcription factors characterized by highly evolutionarily conserved zinc-finger DNA-binding domains. Mouse models have implicated a role of GATA5 during mammalian embryogenesis, including proper heart development and gender-specific regulation of female genitourinary tract formation. Previous studies have found an association of heterozygous missense alterations in GATA5 with a broad variety of heart diseases; however, the clinical relevance of the identified susceptibility variants has remained unclear. Here, we report on a girl with hydrops fetalis, congenital heart defects, clitoromegaly and postnatally increased 17-hydroxyprogesterone levels. By trio whole-exome sequencing, we identified compound heterozygous missense mutations, p.Ser19Trp and p.Arg202Gln, in GATA5 as putative disease-causing alterations. The identified mutations fail to rescue the cardia bifida phenotype in a zebrafish model, mislocalize to subnuclear foci when transiently transfected in HEK293 cells and possess less transcriptional activity. In addition to demonstrating the pathogenicity of identified mutations, our findings show that GATA5 mutations, in addition to heart diseases, can result in congenital abnormalities of the female genitourinary tract in humans.