title: Mutations in KAT6B, encoding a histone acetyltransferase, cause Genitopatellar syndrome.
abstract: Genitopatellar syndrome (GPS) is a skeletal dysplasia with cerebral and genital anomalies for which the molecular basis has not yet been determined. By exome sequencing, we found de novo heterozygous truncating mutations in KAT6B (lysine acetyltransferase 6B, formerly known as MYST4 and MORF) in three subjects; then by Sanger sequencing of KAT6B, we found similar mutations in three additional subjects. The mutant transcripts do not undergo nonsense-mediated decay in cells from subjects with GPS. In addition, human pathological analyses and mouse expression studies point to systemic roles of KAT6B in controlling organismal growth and development. Myst4 (the mouse orthologous gene) is expressed in mouse tissues corresponding to those affected by GPS. Phenotypic differences and similarities between GPS, the Say-Barber-Biesecker variant of Ohdo syndrome (caused by different mutations of KAT6B), and Rubinstein-Taybi syndrome (caused by mutations in other histone acetyltransferases) are discussed. Together, the data support an epigenetic dysregulation of the limb, brain, and genital developmental programs.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Philippe M
authors.initials: PM
authors.lastname: Campeau
authors.forename: Jaeseung C
authors.initials: JC
authors.lastname: Kim
authors.forename: James T
authors.initials: JT
authors.lastname: Lu
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Schwartzentruber
authors.forename: Omar A
authors.initials: OA
authors.lastname: Abdul-Rahman
authors.forename: Silke
authors.initials: S
authors.lastname: Schlaubitz
authors.forename: David M
authors.initials: DM
authors.lastname: Murdock
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Jiang
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lammer
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Enns
authors.forename: William J
authors.initials: WJ
authors.lastname: Rhead
authors.forename: Jon
authors.initials: J
authors.lastname: Rowland
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Bainbridge
authors.forename: Xiang-Jiao
authors.initials: XJ
authors.lastname: Yang
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gingras
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Brendan H
authors.initials: BH
authors.lastname: Lee
mesh_terms: D000015:Abnormalities, Multiple / Q000201:enzymology / Q000235:genetics; D000818:Animals; D016569:Blepharophimosis / Q000201:enzymology / Q000235:genetics; D001763:Blepharoptosis / Q000201:enzymology / Q000235:genetics; D001848:Bone Diseases, Developmental / Q000201:enzymology / Q000235:genetics; D002531:Cerebellum / Q000002:abnormalities; D057890:Epigenomics / Q000379:methods; D059472:Exome; D005260:Female; D006330:Heart Defects, Congenital / Q000201:enzymology / Q000235:genetics; D006579:Heterozygote; D051548:Histone Acetyltransferases / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000201:enzymology / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009139:Musculoskeletal Abnormalities / Q000201:enzymology / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D012415:Rubinstein-Taybi Syndrome / Q000201:enzymology / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods; D014564:Urogenital Abnormalities / Q000201:enzymology / Q000235:genetics*
chemical_list: D051548:Histone Acetyltransferases; C487137:KAT6B protein, human; C496555:Kat6b protein, mouse