A homozygous DPM3 mutation in a patient with alpha-dystroglycan-related limb girdle muscular dystrophy
•Dolichol-P-mannose (DPM) synthase is essential for alpha-dystroglycan O-glycosylation.•DPM synthase is composed of 3 subunits (DPM1, DPM2, and DPM3).•DPM synthase mutations cause congenital muscular dystrophy with or without brain involvement.•Mutations in DPM3 can cause isolated, mild limb girdle...
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creator | Van den Bergh, P.Y.K. Sznajer, Y. Van Parys, V. van Tol, W. Wevers, R.A. Lefeber, D.J. Xu, L. Lek, M. MacArthur, D.G. Johnson, K. Phillips, L. Töpf, A. Straub, V. |
description | •Dolichol-P-mannose (DPM) synthase is essential for alpha-dystroglycan O-glycosylation.•DPM synthase is composed of 3 subunits (DPM1, DPM2, and DPM3).•DPM synthase mutations cause congenital muscular dystrophy with or without brain involvement.•Mutations in DPM3 can cause isolated, mild limb girdle muscular dystrophy.
Defects of O-linked glycosylation of alpha-dystroglycan cause a wide spectrum of muscular dystrophies ranging from severe congenital muscular dystrophy associated with abnormal brain and eye development to mild limb girdle muscular dystrophy. We report a female patient who developed isolated pelvic girdle muscle weakness and wasting, which became symptomatic at age 42. Exome sequencing uncovered a homozygous c.131T > G (p.Leu44Pro) substitution in DPM3, encoding dolichol-P-mannose (DPM) synthase subunit 3, leading to a 50% reduction of enzymatic activity. Decreased availability of DPM as an essential donor substrate for protein O-mannosyltransferase (POMT) 1 and 2 explains defective skeletal muscle alpha-dystroglycan O-glycosylation. Our findings show that DPM3 mutations may lead to an isolated and mild limb girdle muscular dystrophy phenotype without cardiomyopathy. |
doi_str_mv | 10.1016/j.nmd.2017.07.006 |
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Defects of O-linked glycosylation of alpha-dystroglycan cause a wide spectrum of muscular dystrophies ranging from severe congenital muscular dystrophy associated with abnormal brain and eye development to mild limb girdle muscular dystrophy. We report a female patient who developed isolated pelvic girdle muscle weakness and wasting, which became symptomatic at age 42. Exome sequencing uncovered a homozygous c.131T > G (p.Leu44Pro) substitution in DPM3, encoding dolichol-P-mannose (DPM) synthase subunit 3, leading to a 50% reduction of enzymatic activity. Decreased availability of DPM as an essential donor substrate for protein O-mannosyltransferase (POMT) 1 and 2 explains defective skeletal muscle alpha-dystroglycan O-glycosylation. Our findings show that DPM3 mutations may lead to an isolated and mild limb girdle muscular dystrophy phenotype without cardiomyopathy.</description><identifier>ISSN: 0960-8966</identifier><identifier>EISSN: 1873-2364</identifier><identifier>DOI: 10.1016/j.nmd.2017.07.006</identifier><identifier>PMID: 28803818</identifier><language>eng</language><publisher>England: Elsevier B.V</publisher><subject>Alpha-dystroglycan ; Dolichol-P-mannose synthase ; DPM3 ; Dystroglycans - metabolism ; Female ; Homozygote ; Humans ; Limb girdle muscular dystrophy ; Mannosyltransferases - genetics ; Membrane Proteins - genetics ; Middle Aged ; Muscle, Skeletal - diagnostic imaging ; Muscle, Skeletal - pathology ; Muscular Dystrophies, Limb-Girdle - diagnostic imaging ; Muscular Dystrophies, Limb-Girdle - genetics ; Muscular Dystrophies, Limb-Girdle - metabolism ; Muscular Dystrophies, Limb-Girdle - pathology ; Mutation ; Phenotype</subject><ispartof>Neuromuscular disorders : NMD, 2017-11, Vol.27 (11), p.1043-1046</ispartof><rights>2017 Elsevier B.V.</rights><rights>Copyright © 2017 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c353t-f3bd8131105b65132a468ab71f45a79ce63388746c55764ce76b9ff981203f953</citedby><cites>FETCH-LOGICAL-c353t-f3bd8131105b65132a468ab71f45a79ce63388746c55764ce76b9ff981203f953</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.nmd.2017.07.006$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28803818$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Van den Bergh, P.Y.K.</creatorcontrib><creatorcontrib>Sznajer, Y.</creatorcontrib><creatorcontrib>Van Parys, V.</creatorcontrib><creatorcontrib>van Tol, W.</creatorcontrib><creatorcontrib>Wevers, R.A.</creatorcontrib><creatorcontrib>Lefeber, D.J.</creatorcontrib><creatorcontrib>Xu, L.</creatorcontrib><creatorcontrib>Lek, M.</creatorcontrib><creatorcontrib>MacArthur, D.G.</creatorcontrib><creatorcontrib>Johnson, K.</creatorcontrib><creatorcontrib>Phillips, L.</creatorcontrib><creatorcontrib>Töpf, A.</creatorcontrib><creatorcontrib>Straub, V.</creatorcontrib><title>A homozygous DPM3 mutation in a patient with alpha-dystroglycan-related limb girdle muscular dystrophy</title><title>Neuromuscular disorders : NMD</title><addtitle>Neuromuscul Disord</addtitle><description>•Dolichol-P-mannose (DPM) synthase is essential for alpha-dystroglycan O-glycosylation.•DPM synthase is composed of 3 subunits (DPM1, DPM2, and DPM3).•DPM synthase mutations cause congenital muscular dystrophy with or without brain involvement.•Mutations in DPM3 can cause isolated, mild limb girdle muscular dystrophy.
Defects of O-linked glycosylation of alpha-dystroglycan cause a wide spectrum of muscular dystrophies ranging from severe congenital muscular dystrophy associated with abnormal brain and eye development to mild limb girdle muscular dystrophy. We report a female patient who developed isolated pelvic girdle muscle weakness and wasting, which became symptomatic at age 42. Exome sequencing uncovered a homozygous c.131T > G (p.Leu44Pro) substitution in DPM3, encoding dolichol-P-mannose (DPM) synthase subunit 3, leading to a 50% reduction of enzymatic activity. Decreased availability of DPM as an essential donor substrate for protein O-mannosyltransferase (POMT) 1 and 2 explains defective skeletal muscle alpha-dystroglycan O-glycosylation. Our findings show that DPM3 mutations may lead to an isolated and mild limb girdle muscular dystrophy phenotype without cardiomyopathy.</description><subject>Alpha-dystroglycan</subject><subject>Dolichol-P-mannose synthase</subject><subject>DPM3</subject><subject>Dystroglycans - metabolism</subject><subject>Female</subject><subject>Homozygote</subject><subject>Humans</subject><subject>Limb girdle muscular dystrophy</subject><subject>Mannosyltransferases - genetics</subject><subject>Membrane Proteins - genetics</subject><subject>Middle Aged</subject><subject>Muscle, Skeletal - diagnostic imaging</subject><subject>Muscle, Skeletal - pathology</subject><subject>Muscular Dystrophies, Limb-Girdle - diagnostic imaging</subject><subject>Muscular Dystrophies, Limb-Girdle - genetics</subject><subject>Muscular Dystrophies, Limb-Girdle - metabolism</subject><subject>Muscular Dystrophies, Limb-Girdle - pathology</subject><subject>Mutation</subject><subject>Phenotype</subject><issn>0960-8966</issn><issn>1873-2364</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1PAyEURYnR2Fr9AW4MSzdTYZgBJq6a-pnU6ELXhGGYlob5EBjN-Oulqbo0ecljcd4l9wBwjtEcI0yvtvO2qeYpwmyO4iB6AKaYM5KkhGaHYIoKihJeUDoBJ95vEcI5o-wYTFLOEeGYT0G9gJuu6b7GdTd4ePPyRGAzBBlM10LTQgn7-NZtgJ8mbKC0_UYm1eiD69Z2VLJNnLYy6Apa05RwbVxldUzwarDSwT3Zb8ZTcFRL6_XZz56Bt7vb1-VDsnq-f1wuVokiOQlJTcqKY4IxykuaY5LKjHJZMlxnuWSF0pQQzllGVR6bZEozWhZ1XXCcIlIXOZmBy31u77r3QfsgGuOVtla2OhYUuEg52_3AIor3qHKd907XonemkW4UGImdXrEVUa_Y6RUoDqLx5uInfigbXf1d_PqMwPUe0LHkh9FOeBX1KV0Zp1UQVWf-if8G6RyLHg</recordid><startdate>201711</startdate><enddate>201711</enddate><creator>Van den Bergh, P.Y.K.</creator><creator>Sznajer, Y.</creator><creator>Van Parys, V.</creator><creator>van Tol, W.</creator><creator>Wevers, R.A.</creator><creator>Lefeber, D.J.</creator><creator>Xu, L.</creator><creator>Lek, M.</creator><creator>MacArthur, D.G.</creator><creator>Johnson, K.</creator><creator>Phillips, L.</creator><creator>Töpf, A.</creator><creator>Straub, V.</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201711</creationdate><title>A homozygous DPM3 mutation in a patient with alpha-dystroglycan-related limb girdle muscular dystrophy</title><author>Van den Bergh, P.Y.K. ; Sznajer, Y. ; Van Parys, V. ; van Tol, W. ; Wevers, R.A. ; Lefeber, D.J. ; Xu, L. ; Lek, M. ; MacArthur, D.G. ; Johnson, K. ; Phillips, L. ; Töpf, A. ; Straub, V.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-f3bd8131105b65132a468ab71f45a79ce63388746c55764ce76b9ff981203f953</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Alpha-dystroglycan</topic><topic>Dolichol-P-mannose synthase</topic><topic>DPM3</topic><topic>Dystroglycans - metabolism</topic><topic>Female</topic><topic>Homozygote</topic><topic>Humans</topic><topic>Limb girdle muscular dystrophy</topic><topic>Mannosyltransferases - genetics</topic><topic>Membrane Proteins - genetics</topic><topic>Middle Aged</topic><topic>Muscle, Skeletal - diagnostic imaging</topic><topic>Muscle, Skeletal - pathology</topic><topic>Muscular Dystrophies, Limb-Girdle - diagnostic imaging</topic><topic>Muscular Dystrophies, Limb-Girdle - genetics</topic><topic>Muscular Dystrophies, Limb-Girdle - metabolism</topic><topic>Muscular Dystrophies, Limb-Girdle - pathology</topic><topic>Mutation</topic><topic>Phenotype</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Van den Bergh, P.Y.K.</creatorcontrib><creatorcontrib>Sznajer, Y.</creatorcontrib><creatorcontrib>Van Parys, V.</creatorcontrib><creatorcontrib>van Tol, W.</creatorcontrib><creatorcontrib>Wevers, R.A.</creatorcontrib><creatorcontrib>Lefeber, D.J.</creatorcontrib><creatorcontrib>Xu, L.</creatorcontrib><creatorcontrib>Lek, M.</creatorcontrib><creatorcontrib>MacArthur, D.G.</creatorcontrib><creatorcontrib>Johnson, K.</creatorcontrib><creatorcontrib>Phillips, L.</creatorcontrib><creatorcontrib>Töpf, A.</creatorcontrib><creatorcontrib>Straub, V.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Neuromuscular disorders : NMD</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Van den Bergh, P.Y.K.</au><au>Sznajer, Y.</au><au>Van Parys, V.</au><au>van Tol, W.</au><au>Wevers, R.A.</au><au>Lefeber, D.J.</au><au>Xu, L.</au><au>Lek, M.</au><au>MacArthur, D.G.</au><au>Johnson, K.</au><au>Phillips, L.</au><au>Töpf, A.</au><au>Straub, V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A homozygous DPM3 mutation in a patient with alpha-dystroglycan-related limb girdle muscular dystrophy</atitle><jtitle>Neuromuscular disorders : NMD</jtitle><addtitle>Neuromuscul Disord</addtitle><date>2017-11</date><risdate>2017</risdate><volume>27</volume><issue>11</issue><spage>1043</spage><epage>1046</epage><pages>1043-1046</pages><issn>0960-8966</issn><eissn>1873-2364</eissn><abstract>•Dolichol-P-mannose (DPM) synthase is essential for alpha-dystroglycan O-glycosylation.•DPM synthase is composed of 3 subunits (DPM1, DPM2, and DPM3).•DPM synthase mutations cause congenital muscular dystrophy with or without brain involvement.•Mutations in DPM3 can cause isolated, mild limb girdle muscular dystrophy.
Defects of O-linked glycosylation of alpha-dystroglycan cause a wide spectrum of muscular dystrophies ranging from severe congenital muscular dystrophy associated with abnormal brain and eye development to mild limb girdle muscular dystrophy. We report a female patient who developed isolated pelvic girdle muscle weakness and wasting, which became symptomatic at age 42. Exome sequencing uncovered a homozygous c.131T > G (p.Leu44Pro) substitution in DPM3, encoding dolichol-P-mannose (DPM) synthase subunit 3, leading to a 50% reduction of enzymatic activity. Decreased availability of DPM as an essential donor substrate for protein O-mannosyltransferase (POMT) 1 and 2 explains defective skeletal muscle alpha-dystroglycan O-glycosylation. Our findings show that DPM3 mutations may lead to an isolated and mild limb girdle muscular dystrophy phenotype without cardiomyopathy.</abstract><cop>England</cop><pub>Elsevier B.V</pub><pmid>28803818</pmid><doi>10.1016/j.nmd.2017.07.006</doi><tpages>4</tpages></addata></record> |
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subjects | Alpha-dystroglycan Dolichol-P-mannose synthase DPM3 Dystroglycans - metabolism Female Homozygote Humans Limb girdle muscular dystrophy Mannosyltransferases - genetics Membrane Proteins - genetics Middle Aged Muscle, Skeletal - diagnostic imaging Muscle, Skeletal - pathology Muscular Dystrophies, Limb-Girdle - diagnostic imaging Muscular Dystrophies, Limb-Girdle - genetics Muscular Dystrophies, Limb-Girdle - metabolism Muscular Dystrophies, Limb-Girdle - pathology Mutation Phenotype |
title | A homozygous DPM3 mutation in a patient with alpha-dystroglycan-related limb girdle muscular dystrophy |
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