TY - JOUR
T1 - Mutations in KAT6B, encoding a histone acetyltransferase, cause genitopatellar syndrome
AU - Campeau, Philippe M.
AU - Kim, Jaeseung C.
AU - Lu, James T.
AU - Schwartzentruber, Jeremy A.
AU - Abdul-Rahman, Omar A.
AU - Schlaubitz, Silke
AU - Murdock, David M.
AU - Jiang, Ming Ming
AU - Lammer, Edward J.
AU - Enns, Gregory M.
AU - Rhead, William J.
AU - Rowland, Jon
AU - Robertson, Stephen P.
AU - Cormier-Daire, Valérie
AU - Bainbridge, Matthew N.
AU - Yang, Xiang Jiao
AU - Gingras, Marie Claude
AU - Gibbs, Richard A.
AU - Rosenblatt, David S.
AU - Majewski, Jacek
AU - Lee, Brendan H.
N1 - Funding Information:
We thank the families for participating in this study. We thank Alyssa Tran, Stephanie Dugan, and Andrea Kwan for help enrolling subjects; Kyu Sang Joeng, Yangjin Bae, Jianning Tao, and Terry Bertin for help and advice with the experiments; and the University Center for Fetal Medicine of the University of Mississippi for help collecting clinical information. Philippe Campeau is funded in part by the Clinician-Scientist Training award of the Canadian Institutes of Health Research.
PY - 2012/2/10
Y1 - 2012/2/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajhg.2011.11.023
DO - 10.1016/j.ajhg.2011.11.023
M3 - Article
C2 - 22265014
AN - SCOPUS:84862803991
VL - 90
SP - 282
EP - 289
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 2
ER -