Mutations in GDP-mannose pyrophosphorylase b cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan

Keren J. Carss, Elizabeth Stevens, A. Reghan Foley, Sebahattin Cirak, Moniek Riemersma, Silvia Torelli, Alexander Hoischen, Tobias Willer, Monique Van Scherpenzeel, Steven A. Moore, Sonia Messina, Enrico Bertini, Carsten G. Bönnemann, Jose E. Abdenur, Carla M. Grosmann, Akanchha Kesari, Jaya Punetha, Ros Quinlivan, Leigh B. Waddell, Helen K. Young & 16 others Elizabeth Wraige, Shu Yau, Lina Brodd, Lucy Feng, Caroline Sewry, Daniel G. Macarthur, Kathryn N. North, Eric Hoffman, Derek L. Stemple, Matthew E. Hurles, Hans Van Bokhoven, Kevin P. Campbell, Dirk J. Lefeber, Yung Yao Lin, Francesco Muntoni, Scott Wilson

Research output: Contribution to journalArticle

126 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)29-41
Number of pages13
JournalAmerican Journal of Human Genetics
Volume93
Issue number1
DOIs
Publication statusPublished - 11 Jul 2013

Fingerprint

Guanosine Diphosphate Mannose
Dystroglycans
Limb-Girdle Muscular Dystrophies
Glycosylation
Muscular Dystrophies
Mutation
Cytoplasm
Mannosyltransferases
Fibroblasts
Eye Abnormalities
Exome
Muscles
Zebrafish
Missense Mutation
Guanosine Triphosphate
Genes
mannose 1-phosphate guanylyltransferase
Phenotype
Biopsy
Membranes

Cite this

Carss, Keren J. ; Stevens, Elizabeth ; Foley, A. Reghan ; Cirak, Sebahattin ; Riemersma, Moniek ; Torelli, Silvia ; Hoischen, Alexander ; Willer, Tobias ; Van Scherpenzeel, Monique ; Moore, Steven A. ; Messina, Sonia ; Bertini, Enrico ; Bönnemann, Carsten G. ; Abdenur, Jose E. ; Grosmann, Carla M. ; Kesari, Akanchha ; Punetha, Jaya ; Quinlivan, Ros ; Waddell, Leigh B. ; Young, Helen K. ; Wraige, Elizabeth ; Yau, Shu ; Brodd, Lina ; Feng, Lucy ; Sewry, Caroline ; Macarthur, Daniel G. ; North, Kathryn N. ; Hoffman, Eric ; Stemple, Derek L. ; Hurles, Matthew E. ; Van Bokhoven, Hans ; Campbell, Kevin P. ; Lefeber, Dirk J. ; Lin, Yung Yao ; Muntoni, Francesco ; Wilson, Scott. / Mutations in GDP-mannose pyrophosphorylase b cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan. In: American Journal of Human Genetics. 2013 ; Vol. 93, No. 1. pp. 29-41.
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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.",
author = "Carss, {Keren J.} and Elizabeth Stevens and Foley, {A. Reghan} and Sebahattin Cirak and Moniek Riemersma and Silvia Torelli and Alexander Hoischen and Tobias Willer and {Van Scherpenzeel}, Monique and Moore, {Steven A.} and Sonia Messina and Enrico Bertini and B{\"o}nnemann, {Carsten G.} and Abdenur, {Jose E.} and Grosmann, {Carla M.} and Akanchha Kesari and Jaya Punetha and Ros Quinlivan and Waddell, {Leigh B.} and Young, {Helen K.} and Elizabeth Wraige and Shu Yau and Lina Brodd and Lucy Feng and Caroline Sewry and Macarthur, {Daniel G.} and North, {Kathryn N.} and Eric Hoffman and Stemple, {Derek L.} and Hurles, {Matthew E.} and {Van Bokhoven}, Hans and Campbell, {Kevin P.} and Lefeber, {Dirk J.} and Lin, {Yung Yao} and Francesco Muntoni and Scott Wilson",
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Carss, KJ, Stevens, E, Foley, AR, Cirak, S, Riemersma, M, Torelli, S, Hoischen, A, Willer, T, Van Scherpenzeel, M, Moore, SA, Messina, S, Bertini, E, Bönnemann, CG, Abdenur, JE, Grosmann, CM, Kesari, A, Punetha, J, Quinlivan, R, Waddell, LB, Young, HK, Wraige, E, Yau, S, Brodd, L, Feng, L, Sewry, C, Macarthur, DG, North, KN, Hoffman, E, Stemple, DL, Hurles, ME, Van Bokhoven, H, Campbell, KP, Lefeber, DJ, Lin, YY, Muntoni, F & Wilson, S 2013, 'Mutations in GDP-mannose pyrophosphorylase b cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan' American Journal of Human Genetics, vol. 93, no. 1, pp. 29-41. https://doi.org/10.1016/j.ajhg.2013.05.009

Mutations in GDP-mannose pyrophosphorylase b cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan. / Carss, Keren J.; Stevens, Elizabeth; Foley, A. Reghan; Cirak, Sebahattin; Riemersma, Moniek; Torelli, Silvia; Hoischen, Alexander; Willer, Tobias; Van Scherpenzeel, Monique; Moore, Steven A.; Messina, Sonia; Bertini, Enrico; Bönnemann, Carsten G.; Abdenur, Jose E.; Grosmann, Carla M.; Kesari, Akanchha; Punetha, Jaya; Quinlivan, Ros; Waddell, Leigh B.; Young, Helen K.; Wraige, Elizabeth; Yau, Shu; Brodd, Lina; Feng, Lucy; Sewry, Caroline; Macarthur, Daniel G.; North, Kathryn N.; Hoffman, Eric; Stemple, Derek L.; Hurles, Matthew E.; Van Bokhoven, Hans; Campbell, Kevin P.; Lefeber, Dirk J.; Lin, Yung Yao; Muntoni, Francesco; Wilson, Scott.

In: American Journal of Human Genetics, Vol. 93, No. 1, 11.07.2013, p. 29-41.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mutations in GDP-mannose pyrophosphorylase b cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan

AU - Carss, Keren J.

AU - Stevens, Elizabeth

AU - Foley, A. Reghan

AU - Cirak, Sebahattin

AU - Riemersma, Moniek

AU - Torelli, Silvia

AU - Hoischen, Alexander

AU - Willer, Tobias

AU - Van Scherpenzeel, Monique

AU - Moore, Steven A.

AU - Messina, Sonia

AU - Bertini, Enrico

AU - Bönnemann, Carsten G.

AU - Abdenur, Jose E.

AU - Grosmann, Carla M.

AU - Kesari, Akanchha

AU - Punetha, Jaya

AU - Quinlivan, Ros

AU - Waddell, Leigh B.

AU - Young, Helen K.

AU - Wraige, Elizabeth

AU - Yau, Shu

AU - Brodd, Lina

AU - Feng, Lucy

AU - Sewry, Caroline

AU - Macarthur, Daniel G.

AU - North, Kathryn N.

AU - Hoffman, Eric

AU - Stemple, Derek L.

AU - Hurles, Matthew E.

AU - Van Bokhoven, Hans

AU - Campbell, Kevin P.

AU - Lefeber, Dirk J.

AU - Lin, Yung Yao

AU - Muntoni, Francesco

AU - Wilson, Scott

PY - 2013/7/11

Y1 - 2013/7/11

N2 - 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.

AB - 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.

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JF - The American Journal of Human Genetics

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