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3M Syndrome 

3M Syndrome
Chapter:
3M Syndrome
Author(s):

Céline Huber

and Valérie Cormier-Daire

DOI:
10.1093/med/9780199934522.003.0167
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date: 18 October 2018

3M syndrome is an autosomal recessive disorder characterized by pre and postnatal growth retardation, facial dysmorphism, and skeletal changes. 3M syndrome is due to mutations not only in CUL7 but also in OBSL1 and CCDC8. CUL7 plays a scaffold role in E3 ubiquitin ligase complex, composed by heterodimer SKP1-FBXW8 and ROC1, as part of the proteasomal degradation pathway, whose targets include IRS-1, Cyclin D1, GRASP65 and TBC1D3. Unlike other cullins proteins, CUL7 has also non proteolytic functions. The growth-promoting activity of CUL7 is attributed to its ability to bind to p53. Cul7−/− mouse embryos are characterized by IUGR, at late gestational age. These findings suggest a key role of CUL7 in promoting growth at late gestational age and in postnatal life. OBSL1 is highly homologous to the giant muscle protein Obscurin and has been identified as a cytoskeletal adaptor protein. However, its implication in 3M syndrome also indicates a role in the CUL7 ubiquitination pathway.. Moreover, OBSL1 physically interacts with CCDC8 and CUL7 without association between CCDC8 and CUL7, suggesting that OBSL1 may acts as an adaptor protein linking CUL7 and CCDC8. CCDC8 encodes a protein of unknown function. Finally, the alteration in IGFBPs and changes in IGF levels established in 3M fibroblasts, may contribute to the growth restriction of 3M.

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