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Congenital muscular dystrophies involving the O-mannose pathway

Paul T Martin1

  • 1Columbus Children's Research Institute, Department of Pediatrics, Ohio State University, 700 Children's Drive, Columbus, OH 43205, USA. MartinPT@pediatrics.ohio-state.edu

Current Molecular Medicine
|June 23, 2007
PubMed

Insights

Congenital muscular dystrophy (CMD) involves faulty dystroglycan glycosylation. Enhancing this process, even with genes not linked to CMD, shows promise for treating muscular dystrophies.

Area of Science:

  • Biochemistry
  • Genetics
  • Neurology

Background:

  • Congenital muscular dystrophy (CMD) encompasses various forms linked to defective O-mannosyl-linked glycan glycosylation of dystroglycan.
  • At least six genes are implicated in this glycosylation pathway, with defects causing shared muscle and brain pathologies.

Purpose of the Study:

  • To investigate the therapeutic potential of modulating dystroglycan glycosylation in muscular dystrophies.
  • To explore whether enhancing dystroglycan glycosylation can ameliorate disease phenotypes.

Main Methods:

  • Examined the effect of overexpressing the CMD-implicated gene LARGE on dystroglycan glycosylation and function in patient-derived cells.
  • Investigated the impact of overexpressing Galgt2, a non-CMD-associated glycosyltransferase, on dystroglycan glycosylation and its efficacy in a mouse model of Duchenne muscular dystrophy.

Main Results:

  • Overexpression of LARGE restored dystroglycan glycosylation and function in cells from CMD patients.
  • Overexpression of Galgt2 altered dystroglycan glycosylation and significantly inhibited muscular dystrophy in a mouse model.

Conclusions:

  • Modulating dystroglycan glycosylation represents a potential common therapeutic strategy for various muscular dystrophies.
  • Targeting specific glycan structures on dystroglycan may offer a unified approach to treating these debilitating conditions.

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