Mutation in CUL4B, Which Encodes a Member of Cullin-RING Ubiquitin Ligase Complex, Causes X-Linked Mental Retardation

• DOI: 10.1086/512489
• Publication Date: 2007-02-05T13:54:13Z
• Authors: Yongxin Zou; Qiji Liu; Bingxi Chen; Xiyu Zhang; Chenhong Guo; Haibin Zhou; Jiangxia Li; Guimin Gao; Yishou Guo; Chuanzhu Yan; Jianjun Wei; Changshun Shao; Yaoqin Gong
• Keywords: Cullin

We reevaluated a previously reported family with an X-linked mental retardation syndrome and attempted to identify the underlying genetic defect. Screening of candidate genes in a 10-Mb region on Xq25 implicated CUL4B as the causative gene. CUL4B encodes a scaffold protein that organizes a cullin-RING (really interesting new gene) ubiquitin ligase (E3) complex in ubiquitylation. A base substitution, c.1564C-->T, converted a codon for arginine into a premature termination codon, p.R388X, and rendered the truncated peptide completely devoid of the C-terminal catalytic domain. The nonsense mutation also results in nonsense-mediated mRNA decay in patients. In peripheral leukocytes of obligate carriers, a strong selection against cells expressing the mutant allele results in an extremely skewed X-chromosome inactivation pattern. Our findings point to the functional significance of CUL4B in cognition and in other aspects of human development.