Compound heterozygous GATA5 mutations in a girl with hydrops fetalis, congenital heart defects and genital anomalies
| Autor: | Thilo Diehl, Teresa Casar Tena, Maja Hempel, Davor Lessel, Melanie Philipp, Martina S. Burczyk, Tim M. Strom, Christian Kubisch |
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| Rok vydání: | 2017 |
| Předmět: |
Heart Defects
Congenital Male 0301 basic medicine Heterozygote GATA5 Transcription Factor Hydrops Fetalis 030204 cardiovascular system & hematology Clitoromegaly Compound heterozygosity 03 medical and health sciences 0302 clinical medicine Hydrops fetalis Genetics medicine Animals Humans Missense mutation Zebrafish Genetics (clinical) biology Heart development Infant Newborn Heart Genitalia Female medicine.disease biology.organism_classification Phenotype Human genetics Pedigree HEK293 Cells 030104 developmental biology Mutation embryonic structures Female medicine.symptom |
| Zdroj: | Human Genetics. 136:339-346 |
| ISSN: | 1432-1203 0340-6717 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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