Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies

Am J Hum Genet. 2009 Jul;85(1):76-86. doi: 10.1016/j.ajhg.2009.06.006. Epub 2009 Jul 2.

Abstract

Alpha-dystroglycanopathies such as Walker Warburg syndrome represent an important subgroup of the muscular dystrophies that have been related to defective O-mannosylation of alpha-dystroglycan. In many patients, the underlying genetic etiology remains unsolved. Isolated muscular dystrophy has not been described in the congenital disorders of glycosylation (CDG) caused by N-linked protein glycosylation defects. Here, we present a genetic N-glycosylation disorder with muscular dystrophy in the group of CDG type I. Extensive biochemical investigations revealed a strongly reduced dolichol-phosphate-mannose (Dol-P-Man) synthase activity. Sequencing of the three DPM subunits and complementation of DPM3-deficient CHO2.38 cells showed a pathogenic p.L85S missense mutation in the strongly conserved coiled-coil domain of DPM3 that tethers catalytic DPM1 to the ER membrane. Cotransfection experiments in CHO cells showed a reduced binding capacity of DPM3(L85S) for DPM1. Investigation of the four Dol-P-Man-dependent glycosylation pathways in the ER revealed strongly reduced O-mannosylation of alpha-dystroglycan in a muscle biopsy, thereby explaining the clinical phenotype of muscular dystrophy. This mild Dol-P-Man biosynthesis defect due to DPM3 mutations is a cause for alpha-dystroglycanopathy, thereby bridging the congenital disorders of glycosylation with the dystroglycanopathies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dolichol Monophosphate Mannose / metabolism*
  • Dystroglycans / metabolism
  • Female
  • Glycosylation
  • Humans
  • Mannosyltransferases / genetics*
  • Membrane Proteins / genetics*
  • Muscular Dystrophies / genetics*
  • Muscular Dystrophies / metabolism*

Substances

  • Membrane Proteins
  • Dystroglycans
  • Dolichol Monophosphate Mannose
  • Mannosyltransferases
  • DPM3 protein, human