Endocrine Abstracts (2012) 28 OC5.1

Human growth is regulated by an ubiquitination pathway including CUL7, OBSL1 and CCDC8

Dan Hanson1,2, Philip Murray1,2, Tessa Coulson1, Emma Saunders1, Ajibola Omokanye1, Emily Carter1, Amit Sud1,2, Andrew Whatmore1, Graeme Black2 & Peter Clayton1


1Paediatric Endocrinology, University of Manchester, Manchester, United Kingdom; 2Genetic Medicine, University of Manchester, Manchester, United Kingdom.


3-M syndrome is characterised by post-natal growth restriction. We have identified causative mutations in three genes CUL7, OBSL1 and CCDC8. CUL7, a component of an E3 ubiquitin ligase, has a binding domain for p53 and its reduction or absence has a major impact on growth and cell division. OBSL1 is postulated to have a role as a cytoskeletal adaptor, and was not recognised previously to be a growth regulator. The domain structure of CCDC8 predicts a possible role in the regulation of gene expression and it interacts with protein phosphatase 1. We have shown that OBSL1 interacts with both CUL7 and CCDC8 suggesting a shared pathway related to ubiquitination is responsible for the pathogenesis of 3-M. We report a cohort of patients (N=13) with 3-M, 11 CUL7 mutations were identified in 9 patients, 3 OBSL1 mutations in 3 patients and a CCDC8 mutation in one patient. Of the 11 CUL7 mutations 9 were novel and 2 OBSL1 mutations were novel. To isolate the 3-M pathway interactome, V5-OBSL1 or Myc-CUL7 were exogenously expressed in HEK293’s in which we identified co-immunoprecipitated proteins by mass spectrometry. Bioinformatic analysis of the 3-M pathway interaction network revealed splicing machinery, ribosome and cell cycle pathways are particularly enriched. We discovered OBSL1 is part of the CUL7-p53 complex and associates with the mini-chromosome maintenance complex, a regulator of DNA replication. Including this study 3-M has been genetically confirmed in 106 families, 67% (n=71) have CUL7 mutations, 27% (n=29) OBSL1 mutations and 6% (n=6) CCDC8 mutations. The discovery of novel CUL7 and OBSL1 mutations in a cohort of phenotypically identical patients enhances the notion that 3-M syndrome is a disorder of a single pathway. We have also identified novel partners associated with this pathway; the impact of these key cell cycle proteins on human growth now requires investigation.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.

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