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GMPPB ‐Associated Dystroglycanopathy: Emerging Common Variants with Phenotype Correlation
Author(s) -
Jensen Braden S.,
Willer Tobias,
Saade Dimah N.,
Cox Mary O.,
Mozaffar Tahseen,
Scavina Mena,
Stefans Vikki A.,
Winder Thomas L.,
Campbell Kevin P.,
Moore Steven A.,
Mathews Katherine D.
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22898
Subject(s) - biology , phenotype , muscular dystrophy , limb girdle muscular dystrophy , congenital muscular dystrophy , genetics , mutation , gene
Mutations in GDP‐mannose pyrophosphorylase B ( GMPPB ), a catalyst for the formation of the sugar donor GDP‐mannose, were recently identified as a cause of muscular dystrophy resulting from abnormal glycosylation of α‐dystroglycan. In this series, we report nine unrelated individuals with GMPPB ‐associated dystroglycanopathy. The most mildly affected subject has normal strength at 25 years, whereas three severely affected children presented in infancy with intellectual disability and epilepsy. Muscle biopsies of all subjects are dystrophic with abnormal immunostaining for glycosylated α‐dystroglycan. This cohort, together with previously published cases, allows preliminary genotype–phenotype correlations to be made for the emerging GMPPB common variants c.79G>C (p.D27H) and c.860G>A (p.R287Q). We observe that c.79G>C (p.D27H) is associated with a mild limb‐girdle muscular dystrophy phenotype, whereas c.860G>A (p.R287Q) is associated with a relatively severe congenital muscular dystrophy typically involving brain development. Sixty‐six percent of GMPPB families to date have one of these common variants.