Mutations in GDP-Mannose Pyrophosphorylase B Cause Congenital and Limb-Girdle Muscular Dystrophies Associated with Hypoglycosylation of α-Dystroglycan

被引：157

作者：

Carss, Keren J. ^{[1
]}

Stevens, Elizabeth ^{[2
]}

Foley, A. Reghan ^{[2
]}

Cirak, Sebahattin ^{[2
,3
]}

Riemersma, Moniek ^{[4
,5
,6
]}

Torelli, Silvia ^{[2
]}

Hoischen, Alexander ^{[6
]}

Willer, Tobias ^{[7
,8
,9
,10
]}

van Scherpenzeel, Monique ^{[5
]}

Moore, Steven A. ^{[11
]}

Messina, Sonia ^{[12
]}

Bertini, Enrico ^{[13
]}

Boennemann, Carsten G. ^{[14
]}

Abdenur, Jose E. ^{[15
,16
]}

Grosmann, Carla M. ^{[17
,18
]}

Kesari, Akanchha ^{[3
]}

Punetha, Jaya ^{[3
,19
]}

Quinlivan, Ros ^{[2
,20
]}

Waddell, Leigh B. ^{[21
]}

Young, Helen K. ^{[22
,23
]}

Wraige, Elizabeth ^{[24
]}

Yau, Shu ^{[25
]}

Brodd, Lina ^{[25
]}

Feng, Lucy ^{[2
]}

Sewry, Caroline ^{[2
,26
]}

MacArthur, Daniel G. ^{[27
,28
]}

North, Kathryn N. ^{[21
,29
,30
]}

Hoffinan, Eric ^{[3
,19
]}

Stemple, Derek L. ^{[1
]}

Hurles, Matthew E. ^{[1
]}

van Bokhoven, Hans ^{[31
,32
]}

Campbell, Kevin P. ^{[7
,8
,9
,10
]}

Lefeber, Dirk J. ^{[4
,5
]}

Lin, Yung-Yao ^{[1
,33
]}

Muntoni, Francesco ^{[2
]}

机构：

[1] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England

[2] UCL Inst Child Hlth, Dubowitz Neuromuscular Ctr, London WC1N 1EH, England

[3] Childrens Natl Med Ctr, Res Ctr Genet Med, Washington, DC 20010 USA

[4] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, Dept Neurol, NL-6525 HB Nijmegen, Netherlands

[5] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, Dept Lab Med, NL-6525 HB Nijmegen, Netherlands

[6] Radboud Univ Nijmegen, Med Ctr, Inst Genet & Metab Dis, Dept Human Genet,Nijmegen Ctr Mol Life Sci, NL-6500 HB Nijmegen, Netherlands

[7] Univ Iowa, Carver Coll Med, Howard Hughes Med Inst, Iowa City, IA 52242 USA

[8] Univ Iowa, Carver Coll Med, Dept Neurol, Iowa City, IA 52242 USA

[9] Univ Iowa, Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA

[10] Univ Iowa, Carver Coll Med, Dept Mol Physiol & Biophys, Iowa City, IA 52242 USA

[11] Univ Iowa, Carver Coll Med, Dept Pathol, Iowa City, IA 52242 USA

[12] Univ Messina, Azienda Osped Univ Policlin G Martino, Dept Neurosci, I-98125 Messina, Italy

[13] Bambino Gesu Childrens Res Hosp, Mol Med Lab, I-00146 Rome, Italy

[14] NINDS, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA

[15] Childrens Hosp Orange Cty, Div Metab Disorders, Orange, CA 92868 USA

[16] Univ Calif Irvine, Sch Med, Dept Pediat, Irvine, CA 92697 USA

[17] Univ Calif San Diego, Rady Childrens Hosp, Sch Med, Dept Neurosci, San Diego, CA 92123 USA

[18] Univ Calif San Diego, Rady Childrens Hosp, Sch Med, Dept Pediat, San Diego, CA 92123 USA

[19] George Washington Univ, Sch Med & Hlth Sci, Dept Integrat Syst Biol, Washington, DC 20037 USA

[20] Natl Hosp Neurol & Neurosurg, MRC Ctr Neuromuscular Dis, London WC1N 3BG, England

[21] Childrens Hosp Westmead, Inst Neurosci & Muscle Res, Sydney, NSW 2145, Australia

[22] Childrens Hosp Westmead, Dept Neurogenet, Sydney, NSW 2145, Australia

[23] Univ Sydney, Royal N Shore Hosp, Northern Clin Sch, St Leonards, NSW 2065, Australia

[24] Guys & St Thomas NHS Fdn Trust, Evelina Childrens Hosp, Dept Paediat Neurol, London SE1 7EH, England

[25] GSTS Pathol, DNA Lab, London SE1 9RT, England

[26] Robert Jones & Agnes Hunt Orthopaed Hosp NHS Fdn, Wolfson Ctr Inherited Neuromuscular Dis, Oswestry SY10 7AG, Shrops, England

[27] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[28] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA 02142 USA

[29] Univ Sydney, Sydney Med Sch, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia

[30] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia

[31] Radboud Univ Nijmegen, Med Ctr, Nijmegen Ctr Mol Life Sci, Dept Human Genet, NL-6500 HB Nijmegen, Netherlands

[32] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Cognit Neurosci, NL-6500 HB Nijmegen, Netherlands

[33] Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, London E1 2AT, England

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2013年 / 93卷 / 01期

基金：

英国惠康基金;

关键词：

CELL-WALL INTEGRITY; O-GLYCAN STRUCTURES; DEFECTIVE GLYCOSYLATION; ABNORMAL GLYCOSYLATION; GENE; ZEBRAFISH; EXPRESSION; FORM; IDENTIFICATION; DEFICIENCY;

D O I：

10.1016/j.ajhg.2013.05.009

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Congenital muscular dystrophies with hypoglycosylation of alpha-dystroglycan (alpha-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 alpha-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 alpha-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-l-phosphate. GDP-mannose is required for O-mannosylation of proteins, including alpha-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced alpha-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 alpha-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 alpha-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of alpha-DG.

引用

页码：29 / 41

页数：13

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