De novo mutations of the gene encoding the histone acetyltransferase KAT6B cause Genitopatellar syndrome |
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Authors: | Simpson Michael A Deshpande Charu Dafou Dimitra Vissers Lisenka E L M Woollard Wesley J Holder Susan E Gillessen-Kaesbach Gabriele Derks Ronny White Susan M Cohen-Snuijf Ruthy Kant Sarina G Hoefsloot Lies H Reardon Willie Brunner Han G Bongers Ernie M H F Trembath Richard C |
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Institution: | Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, UK. |
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Abstract: | Genitopatellar syndrome (GPS) is a rare disorder in which patellar aplasia or hypoplasia is associated with external genital anomalies and severe intellectual disability. Using an exome-sequencing approach, we identified de novo mutations of KAT6B in five individuals with GPS; a single nonsense variant and three frameshift indels, including a 4 bp deletion observed in two cases. All identified mutations are located within the terminal exon of the gene and are predicted to generate a truncated protein product lacking evolutionarily conserved domains. KAT6B encodes a member of the MYST family of histone acetyltranferases. We demonstrate a reduced level of both histone H3 and H4 acetylation in patient-derived cells suggesting that dysregulation of histone acetylation is a direct functional consequence of GPS alleles. These findings define the genetic basis of GPS and illustrate the complex role of the regulation of histone acetylation during development. |
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