Mutations in KAT6B, Encoding a Histone Acetyltransferase, Cause Genitopatellar Syndrome

详细信息    查看全文

• 作者：Philippe  ; M. Campeau¹ ; ¹⁷ ; Jaeseung  ; C. Kim² ; ¹⁷ ; James  ; T. Lu³ ; ⁴ ; Jeremy  ; A. Schwartzentruber⁵ ; Omar  ; A. Abdul-Rahman⁶ ; Silke Schlaubitz¹ ; David  ; M. Murdock³ ; Ming-Ming Jiang¹ ; Edward  ; J. Lammer⁷ ; Gregory  ; M. Enns⁸ ; William  ; J. Rhead⁹ ; Jon Rowland¹⁰ ; Stephen  ; P. Robertson¹¹ ; Valé ; rie Cormier-Daire¹² ; Matthew  ; N. Bainbridge³ ; ⁴ ; Xiang-Jiao Yang¹³ ; ¹⁴ ; Marie-Claude Gingras¹ ; ³ ; Richard  ; A. Gibbs¹ ; ³ ; David  ; S. Rosenblatt² ; ¹⁴ ; ¹⁵ ; Jacek Majewski² ; ⁵ ; Brendan  ; H. Lee¹ ; ¹⁶ ; ^blee@bcm.edu
• 刊名：The American Journal of Human Genetics
• 出版年：2012
• 出版时间：10 February 2012
• 年：2012
• 卷：90
• 期：2
• 页码：282-289
• 全文大小：1129 K

文摘

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.