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Unlike many other primordial short stature syndromes, intelligence is normal and there is no other major system involvement, indicating that 3\u2010M is predominantly a growth\u2010related condition. From an endocrine perspective, serum GH levels are usually normal and IGF\u2010I normal or low, while growth response to rhGH therapy is variable but typically poor. All these features suggest a degree of resistance in the GH\u2010IGF axis. To date, mutations in three genes <jats:italic>CUL7<\/jats:italic>,<jats:italic> OBSL1<\/jats:italic> and <jats:italic>CCDC8<\/jats:italic> have been shown to cause 3\u2010M. CUL7 acts an ubiquitin ligase and is known to interact with p53, cyclin D\u20101 and the growth factor signalling molecule IRS\u20101, the link with the latter may contribute to the GH\u2010IGF resistance. OBSL1 is a putative cytoskeletal adaptor that interacts with and stabilizes CUL7. CCDC8 is the newest member of the pathway and interacts with OBSL1 and, like CUL7, associates with p53, acting as a co\u2010factor in p53\u2010medicated apoptosis. 3\u2010M patients without a mutation have also been identified, indicating the involvement of additional genes in the pathway. Potentially damaging sequence variants in <jats:italic>CUL7<\/jats:italic> and <jats:italic>OBSL1<\/jats:italic> have been identified in idiopathic short stature (ISS), including those born small with failure of catch\u2010up growth, signifying that the 3\u2010M pathway could play a wider role in disordered growth.<\/jats:p>","DOI":"10.1111\/j.1365-2265.2012.04428.x","type":"journal-article","created":{"date-parts":[[2012,5,25]],"date-time":"2012-05-25T10:58:41Z","timestamp":1337943521000},"page":"335-342","source":"Crossref","is-referenced-by-count":72,"title":["Exploring the spectrum of 3\u2010M syndrome, a primordial short stature disorder of disrupted ubiquitination"],"prefix":"10.1111","volume":"77","author":[{"given":"Peter E.","family":"Clayton","sequence":"first","affiliation":[{"name":"Developmental Biomedicine, Manchester Academic Health Sciences Centre (MAHSC) School of Biomedicine, University of Manchester Manchester UK"},{"name":"Central Manchester University Hospitals Foundation Trust Manchester"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Hanson","sequence":"additional","affiliation":[{"name":"Developmental Biomedicine, Manchester Academic Health Sciences Centre (MAHSC) School of Biomedicine, University of Manchester Manchester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Magee","sequence":"additional","affiliation":[{"name":"Developmental Biomedicine, Manchester Academic Health Sciences Centre (MAHSC) School of Biomedicine, University of Manchester Manchester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip G.","family":"Murray","sequence":"additional","affiliation":[{"name":"Developmental Biomedicine, Manchester Academic Health Sciences Centre (MAHSC) School of Biomedicine, University of Manchester Manchester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma","family":"Saunders","sequence":"additional","affiliation":[{"name":"Developmental Biomedicine, Manchester Academic Health Sciences Centre (MAHSC) School of Biomedicine, University of Manchester Manchester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sayeda N.","family":"Abu\u2010Amero","sequence":"additional","affiliation":[{"name":"Institute of Child Health Baby Bio Bank London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gudrun E.","family":"Moore","sequence":"additional","affiliation":[{"name":"Institute of Child Health, Clinical and Molecular Genetics London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graeme C. 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