De novo mutations of the gene encoding the histone acetyltransferase KAT6B cause genitopatellar syndrome

Michael A. Simpson, Charu Deshpande, Dimitra Dafou, Lisenka E.L.M. Vissers, Wesley J. Woollard, Susan E. Holder, Gabriele Gillessen-Kaesbach, Ronny Derks, Susan M. White, Ruthy Cohen-Snuijf, Sarina G. Kant, Lies H. Hoefsloot, Willie Reardon, Han G. Brunner, Ernie M.H.F. Bongers, Richard C. Trembath*

*Corresponding author for this work
48 Citations (Scopus)

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.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Volume90
Issue number2
Pages (from-to)290-294
Number of pages5
ISSN0002-9297
DOIs
Publication statusPublished - 10.02.2012

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