De Novo Mutations of the Gene Encoding the Histone Acetyltransferase KAT6B Cause Genitopatellar Syndrome

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• 作者：Michael  ; A. Simpson¹ ; ¹¹ ; Charu Deshpande² ; ¹¹ ; Dimitra Dafou¹ ; ¹¹ ; Lisenka  ; E.L.M. Vissers³ ; Wesley  ; J. Woollard¹ ; Susan  ; E. Holder⁴ ; Gabriele Gillessen-Kaesbach⁵ ; Ronny Derks³ ; Susan  ; M. White⁶ ; Ruthy Cohen-Snuijf⁷ ; Sarina  ; G. Kant⁸ ; Lies  ; H. Hoefsloot³ ; Willie Reardon⁹ ; Han  ; G. Brunner³ ; Ernie  ; M.H.F. Bongers³ ; ¹² ; ^{e.bongers@antrg.umcn.nl} ; Richard  ; C. Trembath¹ ; ¹⁰ ; ¹² ; ^{richard.trembath@kcl.ac.uk}
• 刊名：The American Journal of Human Genetics
• 出版年：2012
• 出版时间：10 February 2012
• 年：2012
• 卷：90
• 期：2
• 页码：290-294
• 全文大小：256 K

文摘

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.