title: Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan.
abstract: Congenital muscular dystrophies with hypoglycosylation of α-dystroglycan (α-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of α-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated α-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including α-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced α-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of α-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of α-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-DG.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Keren J
authors.initials: KJ
authors.lastname: Carss
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Stevens
authors.forename: A Reghan
authors.initials: AR
authors.lastname: Foley
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.forename: Moniek
authors.initials: M
authors.lastname: Riemersma
authors.forename: Silvia
authors.initials: S
authors.lastname: Torelli
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Tobias
authors.initials: T
authors.lastname: Willer
authors.forename: Monique
authors.initials: M
authors.lastname: van Scherpenzeel
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.forename: Sonia
authors.initials: S
authors.lastname: Messina
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bönnemann
authors.forename: Jose E
authors.initials: JE
authors.lastname: Abdenur
authors.forename: Carla M
authors.initials: CM
authors.lastname: Grosmann
authors.forename: Akanchha
authors.initials: A
authors.lastname: Kesari
authors.forename: Jaya
authors.initials: J
authors.lastname: Punetha
authors.forename: Ros
authors.initials: R
authors.lastname: Quinlivan
authors.forename: Leigh B
authors.initials: LB
authors.lastname: Waddell
authors.forename: Helen K
authors.initials: HK
authors.lastname: Young
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wraige
authors.forename: Shu
authors.initials: S
authors.lastname: Yau
authors.forename: Lina
authors.initials: L
authors.lastname: Brodd
authors.forename: Lucy
authors.initials: L
authors.lastname: Feng
authors.forename: Caroline
authors.initials: C
authors.lastname: Sewry
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
authors.forename: Eric
authors.initials: E
authors.lastname: Hoffman
authors.forename: Derek L
authors.initials: DL
authors.lastname: Stemple
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
authors.forename: Yung-Yao
authors.initials: YY
authors.lastname: Lin
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
mesh_terms: D000818:Animals; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism*; D005124:Eye Abnormalities / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D056726:Genetic Association Studies / Q000379:methods; D006031:Glycosylation; D006155:Guanosine Diphosphate Mannose / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000201:enzymology / Q000235:genetics*; D020125:Mutation, Missense; D009713:Nucleotidyltransferases / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
chemical_list: C483081:DAG1 protein, human; D049030:Dystroglycans; D006155:Guanosine Diphosphate Mannose; D009713:Nucleotidyltransferases; C026917:mannose 1-phosphate guanylyltransferase