title: De novo mutations of the gene encoding the histone acetyltransferase KAT6B cause Genitopatellar syndrome.
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.
authors.affiliation: Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.forename: Charu
authors.initials: C
authors.lastname: Deshpande
authors.forename: Dimitra
authors.initials: D
authors.lastname: Dafou
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.forename: Wesley J
authors.initials: WJ
authors.lastname: Woollard
authors.forename: Susan E
authors.initials: SE
authors.lastname: Holder
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Ronny
authors.initials: R
authors.lastname: Derks
authors.forename: Susan M
authors.initials: SM
authors.lastname: White
authors.forename: Ruthy
authors.initials: R
authors.lastname: Cohen-Snuijf
authors.forename: Sarina G
authors.initials: SG
authors.lastname: Kant
authors.forename: Lies H
authors.initials: LH
authors.lastname: Hoefsloot
authors.forename: Willie
authors.initials: W
authors.lastname: Reardon
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Ernie M H F
authors.initials: EM
authors.lastname: Bongers
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
mesh_terms: D000107:Acetylation; D000483:Alleles; D000818:Animals; D059472:Exome; D005091:Exons; D005260:Female; D051548:Histone Acetyltransferases / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000201:enzymology / Q000235:genetics; D008297:Male; D051379:Mice; D009139:Musculoskeletal Abnormalities / Q000201:enzymology / Q000235:genetics*; D009154:Mutation; D017422:Sequence Analysis, DNA / Q000379:methods; D014564:Urogenital Abnormalities / Q000201:enzymology / Q000235:genetics*
chemical_list: D006657:Histones; D051548:Histone Acetyltransferases; C487137:KAT6B protein, human; C496555:Kat6b protein, mouse