Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation.
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.
Zou
Yongxin
Y
Key Laboratory for Experimental Teratology of the Ministry of Education, Institute of Medical Genetics, Shandong University School of Medicine, Shandong, China.
Liu
Qiji
Q
Chen
Bingxi
B
Zhang
Xiyu
X
Guo
Chenhong
C
Zhou
Haibin
H
Li
Jiangxia
J
Gao
Guimin
G
Guo
Yishou
Y
Yan
Chuanzhu
C
Wei
Jianjun
J
Shao
Changshun
C
Gong
Yaoqin
Y
D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics*; D044842:Cullin Proteins / Q000235:genetics*; D004303:Dosage Compensation, Genetic; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree
C517832:CUL4B protein, human; D044842:Cullin Proteins