Ubiquitination (Ub) is the process that controls the level and activity of cellular proteins. Mono-ubiquitination of a protein alters its function, while poly-ubiquitination targets a protein for degradation (as the kiss of death). Alterations in the Ub system are associated with a wide range of disease, e.g. cancer, neurological diseases and viral infection.
Disorders of growth where the phenotype is primarily short stature are usually caused by disruption of the GHIGF system or by mutations in genes controlling bone growth. However a murine knock-out of Cullin 7, a component of the E3 ligase of the Ub system, results in significant fetal growth restriction and embryonic lethality. We have now identified mutations in CUL 7 in families with 3-M syndrome, a growth disorder with reduced but proportionate fetal and post-natal growth restriction, indicating that this component of the Ub system is essential to growth. We now show that families with an apparently identical 3-M phenotype can have mutations in OBSL1, a cytoskeletal adaptor protein expressed in cardiac and skeletal muscle, and hitherto not implicated in either growth or the Ub system. CUL7 and OBSL1 appear to act in a common pathway, as knock-out of OBSL1 leads to down-regulation of CUL7, knock-out of CUL7 leads to down-regulation of OBSL1 and co-immunoprecipitation experiments demonstrate that the two proteins physically associate. Children with 3-M syndrome respond poorly to GH treatment: in fibroblasts with a CUL7 mutation, GH signalling through Stat5 and Mapk appears normal, but AKT activation by IGF1 is markedly reduced.
These data indicate that the 3-M syndrome is genetically heterogenous, that disordered ubiquitination with CUL7 mutations causes a primary growth disorder, that OBSL1 is a novel component in this system, and that IGF1 signalling is disrupted. This model growth disorder is providing new avenues to explore in the control of human growth.
Generously supported by the Clinical Endocrinology Trust.