Bicuspid aortic valve (BAV) is the commonest congenital heart disease and a highly heritable trait; however, only the NOTCH1 gene has been linked to limited cases of BAV in humans. Recently, the transcription factor GATA5 has been shown to have an essential role in aortic valve development, and targeted deletion of Gata5 in mice is associated with partially penetrant BAV formation. Here, we investigated the relationship between GATA5 gene variants and BAV with its associated aortopathy. One hundred unrelated individuals with confirmed BAV were prospectively recruited. Following collection of clinical information and DNA extraction, the coding regions and splice signal sequences of the GATA5 gene were screened for sequence variations. The clinical characteristics of the cohort included a male predominance (77%), mean age of diagnosis 29 ± 22 years, associated aortopathy in 59% and positive family history for BAV in 13%. Genetic analysis identified the presence of 4 rare non-synonymous variations within the GATA5 transcriptional activation domains, namely Gln3Arg, Ser19Trp, Tyr142His and Gly166Ser, occurring in one patient each. Gln3Arg and Tyr142His substitutions affect highly conserved and functionally relevant residues, and are likely to impact on the transcriptional activation of GATA5 target regions. A novel Ser19Trp variation was identified at a highly conserved amino acid residue in one patient, while the Gly166Ser variant was found in a familial case of BAV and associated aortopathy. Rare non-synonymous variations in the functionally important GATA5 transcriptional activation domains may be important in the pathogenesis of BAV disease in humans.
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