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

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 identifie... Full description

Journal Title: American journal of human genetics 2013-07-11, Vol.93 (1), p.29-41
Main Author: Carss, Keren J
Other Authors: 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
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0002-9297
Link: https://www.ncbi.nlm.nih.gov/pubmed/23768512
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title: Mutations in GDP-Mannose Pyrophosphorylase B Cause Congenital and Limb-Girdle Muscular Dystrophies Associated with Hypoglycosylation of α-Dystroglycan
format: Article
creator:
  • 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
subjects:
  • Animals
  • Article
  • Child, Preschool
  • DNA Mutational Analysis - methods
  • Dystroglycans - genetics
  • Dystroglycans - metabolism
  • Eye Abnormalities - pathology
  • Female
  • Fibroblasts - enzymology
  • Fibroblasts - pathology
  • Genetic Association Studies - methods
  • Genetics
  • Genetics(clinical)
  • Glycosylation
  • Guanosine Diphosphate Mannose - metabolism
  • Heterozygote
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Muscle, Skeletal - enzymology
  • Muscle, Skeletal - pathology
  • Muscular Dystrophies, Limb-Girdle - enzymology
  • Muscular Dystrophies, Limb-Girdle - genetics
  • Mutation, Missense
  • Nucleotidyltransferases - genetics
  • Nucleotidyltransferases - metabolism
  • Zebrafish - genetics
  • Zebrafish - metabolism
ispartof: American journal of human genetics, 2013-07-11, Vol.93 (1), p.29-41
description: 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.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0002-9297
fulltext: fulltext
issn:
  • 0002-9297
  • 1537-6605
url: Link


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titleMutations in GDP-Mannose Pyrophosphorylase B Cause Congenital and Limb-Girdle Muscular Dystrophies Associated with Hypoglycosylation of α-Dystroglycan
sourceAlma/SFX Local Collection
creatorCarss, 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
creatorcontribCarss, 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 ; UK10K Consortium
descriptionCongenital 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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languageeng
publisherUnited States: Elsevier Inc
subjectAnimals ; Article ; Child, Preschool ; DNA Mutational Analysis - methods ; Dystroglycans - genetics ; Dystroglycans - metabolism ; Eye Abnormalities - pathology ; Female ; Fibroblasts - enzymology ; Fibroblasts - pathology ; Genetic Association Studies - methods ; Genetics ; Genetics(clinical) ; Glycosylation ; Guanosine Diphosphate Mannose - metabolism ; Heterozygote ; Humans ; Infant ; Infant, Newborn ; Male ; Muscle, Skeletal - enzymology ; Muscle, Skeletal - pathology ; Muscular Dystrophies, Limb-Girdle - enzymology ; Muscular Dystrophies, Limb-Girdle - genetics ; Mutation, Missense ; Nucleotidyltransferases - genetics ; Nucleotidyltransferases - metabolism ; Zebrafish - genetics ; Zebrafish - metabolism
ispartofAmerican journal of human genetics, 2013-07-11, Vol.93 (1), p.29-41
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02013 The American Society of Human Genetics
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32013 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved. 2013 The American Society of Human Genetics
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0Carss, Keren J
1Stevens, Elizabeth
2Foley, A. Reghan
3Cirak, Sebahattin
4Riemersma, Moniek
5Torelli, Silvia
6Hoischen, Alexander
7Willer, Tobias
8van Scherpenzeel, Monique
9Moore, Steven A
10Messina, Sonia
11Bertini, Enrico
12Bönnemann, Carsten G
13Abdenur, Jose E
14Grosmann, Carla M
15Kesari, Akanchha
16Punetha, Jaya
17Quinlivan, Ros
18Waddell, Leigh B
19Young, Helen K
20Wraige, Elizabeth
21Yau, Shu
22Brodd, Lina
23Feng, Lucy
24Sewry, Caroline
25MacArthur, Daniel G
26North, Kathryn N
27Hoffman, Eric
28Stemple, Derek L
29Hurles, Matthew E
30van Bokhoven, Hans
31Campbell, Kevin P
32Lefeber, Dirk J
33Lin, Yung-Yao
34Muntoni, Francesco
35UK10K Consortium
title
0Mutations in GDP-Mannose Pyrophosphorylase B Cause Congenital and Limb-Girdle Muscular Dystrophies Associated with Hypoglycosylation of α-Dystroglycan
1American journal of human genetics
addtitleAm J Hum Genet
descriptionCongenital 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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4Dystroglycans - genetics
5Dystroglycans - metabolism
6Eye Abnormalities - pathology
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13Glycosylation
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5Torelli, Silvia
6Hoischen, Alexander
7Willer, Tobias
8van Scherpenzeel, Monique
9Moore, Steven A
10Messina, Sonia
11Bertini, Enrico
12Bönnemann, Carsten G
13Abdenur, Jose E
14Grosmann, Carla M
15Kesari, Akanchha
16Punetha, Jaya
17Quinlivan, Ros
18Waddell, Leigh B
19Young, Helen K
20Wraige, Elizabeth
21Yau, Shu
22Brodd, Lina
23Feng, Lucy
24Sewry, Caroline
25MacArthur, Daniel G
26North, Kathryn N
27Hoffman, Eric
28Stemple, Derek L
29Hurles, Matthew E
30van Bokhoven, Hans
31Campbell, Kevin P
32Lefeber, Dirk J
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titleMutations in GDP-Mannose Pyrophosphorylase B Cause Congenital and Limb-Girdle Muscular Dystrophies Associated with Hypoglycosylation of α-Dystroglycan
authorCarss, 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
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23Muscular Dystrophies, Limb-Girdle - genetics
24Mutation, Missense
25Nucleotidyltransferases - genetics
26Nucleotidyltransferases - metabolism
27Zebrafish - genetics
28Zebrafish - metabolism
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8van Scherpenzeel, Monique
9Moore, Steven A
10Messina, Sonia
11Bertini, Enrico
12Bönnemann, Carsten G
13Abdenur, Jose E
14Grosmann, Carla M
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19Young, Helen K
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24Sewry, Caroline
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26North, Kathryn N
27Hoffman, Eric
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29Hurles, Matthew E
30van Bokhoven, Hans
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1Stevens, Elizabeth
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3Cirak, Sebahattin
4Riemersma, Moniek
5Torelli, Silvia
6Hoischen, Alexander
7Willer, Tobias
8van Scherpenzeel, Monique
9Moore, Steven A
10Messina, Sonia
11Bertini, Enrico
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13Abdenur, Jose E
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15Kesari, Akanchha
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21Yau, Shu
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23Feng, Lucy
24Sewry, Caroline
25MacArthur, Daniel G
26North, Kathryn N
27Hoffman, Eric
28Stemple, Derek L
29Hurles, Matthew E
30van Bokhoven, Hans
31Campbell, Kevin P
32Lefeber, Dirk J
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atitleMutations in GDP-Mannose Pyrophosphorylase B Cause Congenital and Limb-Girdle Muscular Dystrophies Associated with Hypoglycosylation of α-Dystroglycan
jtitleAmerican journal of human genetics
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abstractCongenital 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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pubElsevier Inc
pmid23768512
doi10.1016/j.ajhg.2013.05.009
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