Deficiency of Dol-P-Man Synthase Subunit DPM3 Bridges the Congenital Disorders of Glycosylation with the Dystroglycanopathies

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.

Novel cardiovascular findings in association with a POMT2 mutation: three siblings with α-dystroglycanopathy

“…6 The DPM3 gene, encoding a subunit of DOL-P-Man synthase, was recently associated with CMD in a patient with muscular dystrophy and reduced a-dystroglycan staining but without intellectual disabilities. 9 Finally, mutations in DAG1 encoding a-dystroglycan were identified in a patient with a form of limb girdle muscular dystrophy who had normal brain imaging and relatively mild muscular involvement but intellectual disabilities. 10 POMT2 mutations have been associated with a wide spectrum of phenotypes, including some patients without structural CNS involvement and a more benign course of cognitive impairment and microcephaly.…”

A compound heterozygous mutation in DPAGT1 results in a congenital disorder of glycosylation with a relatively mild phenotype

“…For the most frequent CDG-I subtype, PMM2-CDG (formerly CDG-Ia), several adolescent patients have been reported presenting with cerebellar hypoplasia. 23,24 In addition, DPM3-CDG has been reported in a 27-year-old female with muscle dystrophy and dilated cardiomyopathy, 25 while DOLK-CDG has recently been associated with non-syndromic dilated cardiomyopathy in patients between 5and 18 years of age. 26 Moreover, TUSC3-CDG and MAGT1-CDG are implicated in non-syndromic ID patients, with the age range of 25-62 years.…”

Gènes impliqués dans les alpha-dystroglycanopathies

“…Ces gènes étaient, jusqu'à peu, associés uniquement à des patients CDG (Congenital Disorder of Glycosylation) dont la physiopathologie est liée à des anomalies de la N-Glycosylation. Récemment, leur implication a aussi été montrée dans les anomalies de O-mannosylation suite à l'identification de patients avec un déficit en -DG et une atteinte musculaire (mutation du gène DPM2 chez un patient avec une dystrophie musculaire [49] ; mutation des gènes DOLK [50] ou DPM1 [51] chez des patients avec cardiomyopathie dilatée ; mutation du gène DPM3 chez un patient présentant une clinique mixte dystrophie musculaire et CDG [52]). L'étape commune de synthèse des sucres activés nécessaires à la synthèse des chaînes N-ou O-glycanes, dont le Dol P-Man permet…”