Pathology

  • Mutations in GDP-Mannose Pyrophosphorylase B Cause Congenital and Limb-Girdle Muscular Dystrophies Associated with Hypoglycosylation of α-Dystroglycan.

    GMPPB comp NEW REV 1 

    The muscular dystrophies grouped together as dystroglycanopathies share the common feature of a reduction in a specific, O-mannose-linked glycan that serves as a high affinity receptor for basal laminin proteins such as laminin α2.  Abnormalities in this glycan disrupt the protein interactions that normally link extracellular matrix to intracellular cytoskeleton in striated muscle and key cell types of peripheral nerves and the developing brain.  Genes encoding a wide array of glycosyltransferases and other pathways have previously been reported to cause dystroglycanopathy.  This latest work, published in the American Journal of Human Genetics, reports a cohort of patients with mutations in GMPPB.  This enzyme catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including α-dystroglycan, and it is the substrate of cytosolic mannosyltransferases.  A second paper to be published soon in Molecular Genetics and Metabolism (Yang AC et al., Congenital disorder of glycosylation due to DPM1 mutations presenting with dystroglycanopathy-type congenital muscular dystrophy) reports a patient with mutations in DPM1, a subunit of the dolichol-P mannose synthase complex that is immediately downstream of GMPPB.  This complex produces dol-P-mannose, the donor substrate for various glycosylation processes, including the O-mannosylation of α-dystroglycan.

    This work expands the genotypic spectrum of dystroglycanopathies.  Dr. Kevin Campbell’s Howard Hughes Medical Institute research laboratory and the Iowa Wellstone Muscular Dystrophy Cooperative Research Center co-Directed by Drs. Campbell and Steven Moore have played key roles identifying patients with dystroglycanopathy and discovering the genes responsible for the glycosylation defects that result in muscular dystrophies across a wide range of clinical severities.  With the publication of GMPPB and DPM1, the total number of dystroglycanopathy genes has now reached fifteen.

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     PubMed