What causes classic congenital muscular dystrophy (CMD)?

Updated: Jul 03, 2019
  • Author: Emad R Noor, MBChB; Chief Editor: Amy Kao, MD  more...
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Answer

This is an autosomal recessive disease caused by a mutation on chromosome 6 in the LAMA2 gene that codes for laminin-α2.

More than 90 different missense, nonsense, splice-site, and deletion mutations have been described.

Expression of laminin-α2 is related to disease severity. Complete lack of expression is always associated with a severe phenotype. Partial loss of expression is often associated with a mild phenotype, but severe phenotypes have also been described.

Laminin-α2 is expressed in the basement membrane of striated muscle, cerebral blood vessels, Schwann cells, and skin.

Laminins are glycoproteins that form the backbone of the basement membrane in almost every cell type.

  • Twelve laminin genes (5 alpha, 4 beta, 3 gamma) are known.

  • Each laminin is a heterotrimer (alpha-beta-gamma). Laminin 2 (α2-beta1-gamma1) and laminin 4 (α2-β2-γ1) are expressed in muscle.

  • Laminins bind to a number of molecules, most importantly to the extracellular matrix proteins neurexin, agrin and collagen VI and to the transmembrane proteins α-dystroglycan, integrins and syndecans.

  • They are thought to play a role in cell-to-cell recognition, cell shape, differentiation, movement, transmission of force, and tissue survival.

  • Loss of laminin-α2 results in a secondary loss of α-dystroglycan and integrin-α7 (not dystrophin or sarcoglycans), with resultant impairment of myogenesis, synaptogenesis, force generation, and mechanical stability.


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