Congenital muscular dystrophy and generalized epilepsy caused by GMPPB mutations.
The alpha-dystroglycanopathies are genetically heterogeneous muscular dystrophies that result from hypoglycosylation of alpha-dystroglycan (α-DG). Alpha-dystroglycan is an essential link between the extracellular matrix and the muscle fiber sarcolemma, and proper glycosylation is critical for its ability to bind to ligands in the extracellular matrix. We sought to identify the genetic basis of alpha-dystroglycanopathy in a family wherein the affected individuals presented with congenital muscular dystrophy, brain abnormalities and generalized epilepsy. We performed whole exome sequencing and identified compound heterozygous GMPPB mutations in the affected children. GMPPB is an enzyme in the glycosylation pathway, and GMPPB mutations were recently linked to eight cases of alpha-dystroglycanopathy with a range of symptoms. We identified a novel mutation in GMPPB (p.I219T) as well as a previously published mutation (p.R287Q). Thus, our work further confirms a role for GMPPB defects in alpha-dystroglycanopathy, and suggests that glycosylation may play a role in the neuronal membrane channels or networks involved in the physiology of generalized epilepsy syndromes. This article is part of a Special Issue entitled RNA Metabolism 2013.
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Alya R
AR
Raphael
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Julien
J
Couthouis
Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA.
Sarada
S
Sakamuri
Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA; Neuroscience Center, Stanford Hospital and Clinics, Stanford, CA, USA.
Carly
C
Siskind
Departments of Pathology and Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
Hannes
H
Vogel
Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA.
John W
JW
Day
Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: agitler@stanford.edu.
Aaron D
AD
Gitler
D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004829:Epilepsy, Generalized / Q000235:genetics*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D009154:Mutation; D009713:Nucleotidyltransferases / Q000235:genetics*; D010375:Pedigree; D058494:Walker-Warburg Syndrome / Q000235:genetics*
D009713:Nucleotidyltransferases; C026917:mannose 1-phosphate guanylyltransferase
Alpha-dystroglycanopathies; Epilepsy; Exome sequencing; GMPPB; Glycosylation; Muscular dystrophy