Compound heterozygous GATA5 mutations in a girl with hydrops fetalis, congenital heart defects and genital anomalies.
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.
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Maja
M
Hempel
Institute for Biochemistry and Molecular Biology, Ulm University, 89081, Ulm, Germany.
Teresa
T
Casar Tena
Department of Paediatrics, Neonatal Intensive Care Unit, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Thilo
T
Diehl
Institute for Biochemistry and Molecular Biology, Ulm University, 89081, Ulm, Germany.
Martina S
MS
Burczyk
Institute of Human Genetics, Helmholtz Zentrum München, 85764, Neuherberg, Germany.|Institute of Human Genetics, Technical University of Munich, 81675, Munich, Germany.
Tim M
TM
Strom
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany.
Christian
C
Kubisch
Institute for Biochemistry and Molecular Biology, Ulm University, 89081, Ulm, Germany. melanie.philipp@uni-ulm.de.
Melanie
M
Philipp
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. d.lessel@uke.de.
Davor
D
Lessel
D000818:Animals; D005260:Female; D050992:GATA5 Transcription Factor / Q000235:genetics*; D005836:Genitalia, Female / Q000002:abnormalities*; D057809:HEK293 Cells; D006321:Heart / Q000196:embryology; D006330:Heart Defects, Congenital / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D015160:Hydrops Fetalis / Q000235:genetics*; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010375:Pedigree; D015027:Zebrafish / Q000196:embryology
D050992:GATA5 Transcription Factor; C494755:GATA5 protein, human