3M syndrome is characterised by severe intra-uterine and post-natal growth failure. Patients have a characteristic triangular facial appearance and disproportionate short stature with tall vertebral bodies and over-tubulation of long bones. The condition bears some resemblance to the Russell Silver syndrome, but is transmitted as an autosomal recessive trait. It has been proposed that heterozygous carriers demonstrate mild phenotypic manifestations of the condition.
3M syndrome has been reported in a wide range of populations. We identified the condition within a very large, highly consanguinous pedigree in North-East Brazil that was under study because of a high incidence of severe isolated GH deficiency due to homozygous mutation in the GHRH-receptor gene. Autozygosity mapping in this and other families with multiple affected sibs identified a locus on chromosome 6p21.1. Genetic analysis refined the interval of interest, and sequencing of individual genes in this region led to the identification of pathogenic mutations within Cullin 7 (Huber et al Nat Genet 2005).
Cullin 7 is one member of a family of proteins involved in cell cycle regulation, including acting as a scaffold for the assembly of the E3 ligase enzyme complex that leads to the ubiquitination of substrate protein as a prelude to their degradation in 26S proteasomes. The Brazilian 3M subjects carry a missense mutation in exon 25 of Cullin 7 creating a premature stop codon (4717C>T, R1573X). This region is necessary for ROC1 recruitment and binding, and thus formation of the E3 ligase complex.
These investigations demonstrate that mutations in Cullin 7 cause 3M syndrome and suggest that a defect in ubiquitination generates both pre- and post-natal growth retardation.
01 - 05 Apr 2006
European Society of Endocrinology