The genetics of 3-M syndrome: unravelling a potential new regulatory growth pathway

Horm Res Paediatr. 2011;76(6):369-78. doi: 10.1159/000334392. Epub 2011 Nov 29.


3-M syndrome is an autosomal recessive primordial growth disorder characterised by severe postnatal growth restriction caused by mutations in CUL7, OBSL1 or CCDC8. Clinical characteristics include dysmorphic facial features and fleshy prominent heels with a variable degree of radiological abnormalities. CUL7 is a structural protein central to the formation of an ubiquitin E3 ligase that is known to target insulin receptor substrate 1 for degradation. CUL7 also binds to p53 and may be involved in the control of p53-dependent apoptosis. OBSL1 is a cytoskeletal adaptor protein that was thought to play a central role in myocyte remodelling, and CCDC8 has no defined function as yet. However, the physical interaction of OBSL1 with both CUL7 and CCDC8 and its potential role in the regulation of CUL7 expression suggest all three proteins are members of the same growth-regulatory pathway. Future work should be directed to investigating the function of the 3-M syndrome pathway and in particular the role in the insulin like growth factor I signalling pathway with a view of potentially revealing new therapeutic targets and identifying key regulators of cellular growth.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adolescent
  • Adolescent Development*
  • Animals
  • Body Height
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Child
  • Child Development*
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism*
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Dwarfism / genetics*
  • Dwarfism / metabolism*
  • Dwarfism / physiopathology
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / metabolism*
  • Intellectual Disability / physiopathology
  • Muscle Hypotonia / genetics*
  • Muscle Hypotonia / metabolism*
  • Muscle Hypotonia / physiopathology
  • Mutant Proteins / metabolism
  • Silver-Russell Syndrome / genetics
  • Silver-Russell Syndrome / metabolism
  • Silver-Russell Syndrome / physiopathology
  • Spine / abnormalities
  • Spine / metabolism
  • Spine / physiopathology


  • CCDC8 protein, human
  • CUL7 protein, human
  • Carrier Proteins
  • Cullin Proteins
  • Cytoskeletal Proteins
  • Mutant Proteins
  • OBSL1 protein, human

Supplementary concepts

  • Miller-McKusick-Malvaux-Syndrome (3M Syndrome)