title: GMPPB-Associated Dystroglycanopathy: Emerging Common Variants with Phenotype Correlation.
abstract: 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.
authors: Departments of Pediatrics and Neurology, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors: Braden S
authors: BS
authors: Jensen
authors: Howard Hughes Medical Institute, Departments of Molecular Physiology and Biophysics, Neurology, and Internal Medicine, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors: Tobias
authors: T
authors: Willer
authors: Departments of Pediatrics and Neurology, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors: Dimah N
authors: DN
authors: Saade
authors: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors: Mary O
authors: MO
authors: Cox
authors: Departments of Neurology and Orthopaedic Surgery, University of California, Irvine, California.
authors: Tahseen
authors: T
authors: Mozaffar
authors: Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware.
authors: Mena
authors: M
authors: Scavina
authors: Departments of Pediatrics and Physical Medicine and Rehabilitation, University of Arkansas for Medical Sciences College of Medicine, Little Rock, Arkansas.
authors: Vikki A
authors: VA
authors: Stefans
authors: Invitae Corp, San Francisco, California.|Prevention Genetics, Marshfield, Wisconsin.
authors: Thomas L
authors: TL
authors: Winder
authors: Howard Hughes Medical Institute, Departments of Molecular Physiology and Biophysics, Neurology, and Internal Medicine, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, Iowa.
authors: Kevin P
authors: KP
authors: Campbell
authors: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors: Steven A
authors: SA
authors: Moore
authors: Departments of Pediatrics and Neurology, University of Iowa Carver College of Medicine, Iowa City, Iowa.
authors: Katherine D
authors: KD
authors: Mathews
mesh_terms: D000293:Adolescent; D000483:Alleles; D001706:Biopsy; D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D049030:Dystroglycans / Q000378:metabolism*; D005260:Female; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D009713:Nucleotidyltransferases / Q000235:genetics*; D010641:Phenotype; D055815:Young Adult
chemical_list: D049030:Dystroglycans; D009713:Nucleotidyltransferases; C026917:mannose 1-phosphate guanylyltransferase
keywords: GMPPB; congenital muscular dystrophy; congenital myasthenic syndrome; dystroglycanopathy; limb-girdle muscular dystrophy