3-M syndrome is an autosomal recessive primordial growth disorder characterized by pre- and post-natal growth restriction, facial dysmorphism and radiological abnormalities. Mutations in the gene CUL7 have been previously shown to cause 3-M syndrome. CUL7 is a member of the cullin family of E3 ubiquitin ligases involved in targeted protein degradation.
We identified a large cohort of 3-M syndrome patients who did not carry CUL7 mutations but shared the same distinctive phenotypic features. Genome wide high density SNP mapping identified a second locus on chromosome 2q35q36.1. Subsequent candidate gene analysis led to the identification of 7 distinct null mutations from 10 families within the gene encoding Obscurin like-1 (OBSL1).
OBSL1 is a putative cytoskeletal adaptor protein which we have shown localizes to the nuclear envelope and is homologous to the giant sarcomere protein Obscurin.
We have been able to demonstrate that OBSL1 interacts with CUL7 by co-immunoprecipitation of transiently expressed HEK293 cells. In addition knockdown of OBSL1 by siRNA in these cells leads to the concomitant loss of CUL7. Morpholino (antisense oligonucleotide) induced knockdown of the Obsl1 ortholog in Xenopus tropicalis causes significant growth restriction but otherwise phenotypically normal tadpoles at embryonic stage 50 (14 days).
To our knowledge we report the first identification of mutations in OBSL1 and first involvement of a cytoskeletal adaptor protein in a human growth disorder. Our findings imply that CUL7 and OBSL1 are involved in the same molecular pathway and this pathway is a key regulator of human growth. A small cohort of 3-M syndrome patients with neither CUL7 nor OBSL1 mutations has also been identified suggesting a third gene is likely to be involved in the CUL7/OBSL1 pathway.
10 - 12 Nov 2009
British Society for Paediatric Endocrinology and Diabetes