Abstract
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.
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Acknowledgements
We are thankful to the family members for participation, and Sandra Burczyk and Carina Riedmüller for excellent zebrafish care. The lab of MP is supported by grants from the Deutsche Forschungsgemeinschaft (PH144/4-1) and the Boehringer Ingelheim Ulm Initiative (C9). TCT and MSB were scholars of the International Graduate School in Molecular Medicine at Ulm University (funded by the German Excellence Initiative of the DFG).
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The Ethical Board of the Medical Faculty of the Hamburg University approved the study. The study was performed in accordance with the Declaration of Helsinki protocols.
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All biological samples were obtained following written informed consent from studied individuals or their legal representatives.
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M. Hempel and T. Casar Tena contributed equally to this work and should be regarded as joint first authors.
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Hempel, M., Casar Tena, T., Diehl, T. et al. Compound heterozygous GATA5 mutations in a girl with hydrops fetalis, congenital heart defects and genital anomalies. Hum Genet 136, 339–346 (2017). https://doi.org/10.1007/s00439-017-1762-2
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DOI: https://doi.org/10.1007/s00439-017-1762-2