[PDF][PDF] Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation

Y Zou, Q Liu, B Chen, X Zhang, C Guo, H Zhou… - The American Journal of …, 2007 - cell.com
Y Zou, Q Liu, B Chen, X Zhang, C Guo, H Zhou, J Li, G Gao, Y Guo, C Yan, J Wei, C Shao
The American Journal of Human Genetics, 2007cell.com
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 …
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.
cell.com