What causes LARGE congenital muscular dystrophy (MDDGA6)?

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

This autosomal recessive disease is due to a mutation in a putative glycosyltransferase that is homologous to the mutation in the myodystrophy mouse (LARGEmyd). Like fukutin and POMGnT1, LARGE is also localized to the Golgi apparatus. However, when mutated, it localizes to the endoplasmic reticulum and, like FKRP, is likely then targeted for degradation.

The LARGEmyd mice have a severe progressive muscular dystrophy, mild cardiomyopathy, retinal involvement, and CNS involvement.

Muscle biopsy samples from 1 patient with a mutation in LARGE showed reduced immunostaining for α-dystroglycan, reduced molecular weight of α-dystroglycan, and impaired laminin-α2 binding.

Modulation of LARGE expression or activity may be a feasible therapeutic strategy for persons with glycosyltransferase-deficient congenital muscular dystrophies.

  • Interaction of LARGE with the N-terminal domain of α-dystroglycan is an essential step for substrate recognition necessary to initiate functional glycosylation.

  • Overexpression of LARGE ameliorates the dystrophic phenotype of LARGEmyd mice and induces the synthesis of glycan-enriched α-dystroglycan with high affinity for extracellular ligands.

  • Gene transfer of LARGE into the cells of individuals with several different congenital muscular dystrophies restores α-dystroglycan receptor function and allows glycan-enriched α-dystroglycan to coordinate laminin organization on the cell surface.


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