The gene CUL7 encodes for a component of SCF-like E3 ubiquitin-protein ligase complex, which interacts with TP53, CUL9, and FBXW8 proteins. Such complexes usually mediate the ubiquitination and subsequent proteasomal degradation of target proteins. In the case of CUL7, target proteins are likely to be involved in endothelial proliferation and/or differentiation. In fact CUL7 was found to be involved in chondrocyte growth and proliferation. CUL7 has a central DOC domain and a C-terminal cullin domain, in addition to these a 72-amino acid domain enriched in glycine and acidic residues is located at the N-terminus of CUL7. The latter also contains an ATP/GTP-binding site motif A and motifs found in mitochondrial energy transfer proteins. CUL7 is usually expressed in a wide range of tissues and cell lines except testis and small intestine.
The gene CUL7 is mapped to chromosome 6, it spans over 16 Kb. CUL7 mutations can lead to reduced cell mitosis during the early gestation period and consequently retarded growth, which is the central feature of the 3M syndrome-1. These mutations may disrupt the ability of CUL7 to assemble the components of the ubiquitin-proteasome system. Therefore, impaired ubiquitination may have a role in the pathogenesis of intrauterine growth retardation.
Al-Dosari et al. (2012) characterized a cohort of 14 patients 3M syndrome born to six consanguineous Saudi families (A-F). Despite their typical and easily discernible clinical phenotype, all these patients have been extensively investigated for alternative causes of their short stature and received erroneous diagnoses. Genomic DNA analysis revealed the presence of a novel CUL7 acceptor splice site mutation (c.2863-1G>C) in two sisters (4 and 2 years old, respectively) in family A, which resulted in activation of two cryptic splice sites and production of two aberrant transcripts. The first transcript lacks 31bp of exon 15 and the second lacks the entire exon 15 (176 bp); both transcripts predict premature termination (p.G955RfsX3 and p.G955TfsX13). In family B, two siblings, a 4-year-old girl and her 14-month-old brother born to healthy second-cousin Saudi parents, a novel nonsense mutation in exon 4 of CUL7 was identified (c.1144C>T, pR382X). Results of DNA analysis in four patients, including an 8-year-old boy, from family C revealed the presence of a third novel nonsense mutation in exon 15 of CUL7 (c.2988G>A, pW996X).