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- DOI: 10.1038/ng1628
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Identification of mutations in CUL7 in 3-M syndrome.
Huber, C, Dias-Santagata, D, Glaser, A, O'Sullivan, J, Brauner, R, Wu, K, Xu, X, Pearce, K, Wang, R, Uzielli, M, Dagoneau, N, Chemaitilly, W, Superti-Furga, A, Dos Santos, H, Mégarbané, A, Morin, G, Gillessen-Kaesbach, G, Hennekam, R, Van der Burgt, I, Black, GCM, Clayton, PE, Read, A, Le Merrer, M, Scambler, P, Munnich, A, Pan, Z, Winter, R, Cormier-Daire, V
Nat Genet. 2005;37( 10):1119-24.
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Full-text held externally
- DOI: 10.1038/ng1628
Abstract
Intrauterine growth retardation is caused by maternal, fetal or placental factors that result in impaired endovascular trophoblast invasion and reduced placental perfusion. Although various causes of intrauterine growth retardation have been identified, most cases remain unexplained. Studying 29 families with 3-M syndrome (OMIM 273750), an autosomal recessive condition characterized by severe pre- and postnatal growth retardation, we first mapped the underlying gene to chromosome 6p21.1 and then identified 25 distinct mutations in the gene cullin 7 (CUL7). CUL7 assembles an E3 ubiquitin ligase complex containing Skp1, Fbx29 (also called Fbw8) and ROC1 and promotes ubiquitination. Using deletion analysis, we found that CUL7 uses its central region to interact with the Skp1-Fbx29 heterodimer. Functional studies indicated that the 3-M-associated CUL7 nonsense and missense mutations R1445X and H1464P, respectively, render CUL7 deficient in recruiting ROC1. These results suggest that impaired ubiquitination may have a role in the pathogenesis of intrauterine growth retardation in humans.
Keyword(s)
Child; Chromosome Mapping; Codon, Nonsense; DNA Mutational Analysis; Female; Homozygote; Humans; Male; Mutation, Missense; Protein Interaction Mapping; Protein Structure, Tertiary; Research Support, Non-U.S. Gov't; Sequence Deletion; Syndrome; genetics: Chromosomes, Human, Pair 6; genetics: Cullin Proteins; genetics: Fetal Growth Retardation; metabolism: Carrier Proteins; metabolism: S-Phase Kinase-Associated Proteins; metabolism: SKP Cullin F-Box Protein Ligases