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

Am J Hum Genet. 2012 Feb 10;90(2):290-4. doi: 10.1016/j.ajhg.2011.11.024. Epub 2012 Jan 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Alleles
  • Animals
  • Exome
  • Exons
  • Female
  • Histone Acetyltransferases / genetics*
  • Histones / metabolism
  • Humans
  • Intellectual Disability / enzymology
  • Intellectual Disability / genetics
  • Male
  • Mice
  • Musculoskeletal Abnormalities / enzymology
  • Musculoskeletal Abnormalities / genetics*
  • Mutation*
  • Sequence Analysis, DNA / methods
  • Urogenital Abnormalities / enzymology
  • Urogenital Abnormalities / genetics*

Substances

  • Histones
  • Histone Acetyltransferases
  • KAT6B protein, human
  • Kat6b protein, mouse