A gain‐of‐glycosylation mutation associated with myoclonus‐dystonia syndrome affects trafficking and processing of mouse ε‐sarcoglycan in the late secretory pathway
Identifieur interne : 001591 ( Main/Exploration ); précédent : 001590; suivant : 001592A gain‐of‐glycosylation mutation associated with myoclonus‐dystonia syndrome affects trafficking and processing of mouse ε‐sarcoglycan in the late secretory pathway
Auteurs : Adrian Waite [Royaume-Uni] ; Maria Cristina De Rosa [Italie] ; Andrea Brancaccio [Italie] ; Derek J. Blake [Royaume-Uni]Source :
- Human Mutation [ 1059-7794 ] ; 2011-11.
English descriptors
- Teeft :
- Amino, Asparagine, Biol, Biotinylated, Biotinylation, Carvalho aguiar, Cell surface, Chloroquine, Control experiments, Degradation, Deletion, Dystonia, Dystroglycan, Ectodomain, Ectopic, Ectopic glycan, Endo, Erad, Esapa, Extracellular, Extracellular region, Genet, Glycan, Glycosylation, Human mutation, Immunoprecipitated, Intracellular, Klein, Late secretory pathway, Leupeptin, Lysosomal, Lysosomal degradation, Lysosome, Missense, Missense mutations, Murine, Muscular dystrophy, Mutant, Mutant protein, Mutation, Neurology, Ozelius, Pathway, Plasma membrane, Pngase, Protein levels, Proteolytic, Proteolytic processing, Quality control, Receptor, Sarcoglycan, Secretory, Secretory pathway, Sgce, Supp, Transfected, Transfected cells, Untreated, Vogt.
Abstract
Missense mutations in the SGCE gene encoding ε‐sarcoglycan account for approximately 15% of SGCE‐positive cases of myoclonus‐dystonia syndrome (MDS) in humans. In this study, we show that while the majority of MDS‐associated missense mutants modeled with a murine ε‐sarcoglycan cDNA are substrates for endoplasmic reticulum‐associated degradation, one mutant, M68T (analogous to human c.275T>C, p.M92T), located in the Ig‐like domain of ε‐sarcoglycan, results in a gain‐of‐glycosylation mutation producing a protein that is targeted to the plasma membrane, albeit at reduced levels compared to wild‐type ε‐sarcoglycan. Removal of the ectopic N‐linked glycan failed to restore efficient plasma membrane targeting of M68T demonstrating that the substitution rather than the glycan was responsible for the trafficking defect of this mutant. M68T also colocalized with CD63‐positive vesicles in the endosomal–lysosomal system and was found to be more susceptible to lysosomal proteolysis than wild‐type ε‐sarcoglycan. Finally, we demonstrate impaired ectodomain shedding of M68T, a process that occurs physiologically for ε‐sarcoglycan resulting in the lysosomal trafficking of the intracellular C‐terminal domain of the protein. Our findings show that functional analysis of rare missense mutations can provide a mechanistic insight into the pathogenesis of MDS and the physiological role of ε‐sarcoglycan. Hum Mutat 32:1246–1258, 2011. ©2011 Wiley Periodicals, Inc.
Url:
DOI: 10.1002/humu.21561
Affiliations:
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Blake</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Psychological Medicine and Neurology, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Heath Park, Cardiff</wicri:regionArea><wicri:noRegion>Cardiff</wicri:noRegion></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Royaume-Uni</country></affiliation><affiliation wicri:level="1"><country xml:lang="fr" wicri:curation="lc">Royaume-Uni</country><wicri:regionArea>Correspondence address: Department of Psychological Medicine and Neurology, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Henry Wellcome Building for Biomedical Research in Wales, Heath Park, Cardiff, CF14 4XN</wicri:regionArea><wicri:noRegion>CF14 4XN</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Human Mutation</title><title level="j" type="alt">HUMAN MUTATION</title><idno type="ISSN">1059-7794</idno><idno type="eISSN">1098-1004</idno><imprint><biblScope unit="vol">32</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="1246">1246</biblScope><biblScope unit="page" to="1258">1258</biblScope><biblScope unit="page-count">13</biblScope><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2011-11">2011-11</date></imprint><idno type="ISSN">1059-7794</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1059-7794</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Amino</term><term>Asparagine</term><term>Biol</term><term>Biotinylated</term><term>Biotinylation</term><term>Carvalho aguiar</term><term>Cell surface</term><term>Chloroquine</term><term>Control experiments</term><term>Degradation</term><term>Deletion</term><term>Dystonia</term><term>Dystroglycan</term><term>Ectodomain</term><term>Ectopic</term><term>Ectopic glycan</term><term>Endo</term><term>Erad</term><term>Esapa</term><term>Extracellular</term><term>Extracellular region</term><term>Genet</term><term>Glycan</term><term>Glycosylation</term><term>Human mutation</term><term>Immunoprecipitated</term><term>Intracellular</term><term>Klein</term><term>Late secretory pathway</term><term>Leupeptin</term><term>Lysosomal</term><term>Lysosomal degradation</term><term>Lysosome</term><term>Missense</term><term>Missense mutations</term><term>Murine</term><term>Muscular dystrophy</term><term>Mutant</term><term>Mutant protein</term><term>Mutation</term><term>Neurology</term><term>Ozelius</term><term>Pathway</term><term>Plasma membrane</term><term>Pngase</term><term>Protein levels</term><term>Proteolytic</term><term>Proteolytic processing</term><term>Quality control</term><term>Receptor</term><term>Sarcoglycan</term><term>Secretory</term><term>Secretory pathway</term><term>Sgce</term><term>Supp</term><term>Transfected</term><term>Transfected cells</term><term>Untreated</term><term>Vogt</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Missense mutations in the SGCE gene encoding ε‐sarcoglycan account for approximately 15% of SGCE‐positive cases of myoclonus‐dystonia syndrome (MDS) in humans. In this study, we show that while the majority of MDS‐associated missense mutants modeled with a murine ε‐sarcoglycan cDNA are substrates for endoplasmic reticulum‐associated degradation, one mutant, M68T (analogous to human c.275T>C, p.M92T), located in the Ig‐like domain of ε‐sarcoglycan, results in a gain‐of‐glycosylation mutation producing a protein that is targeted to the plasma membrane, albeit at reduced levels compared to wild‐type ε‐sarcoglycan. Removal of the ectopic N‐linked glycan failed to restore efficient plasma membrane targeting of M68T demonstrating that the substitution rather than the glycan was responsible for the trafficking defect of this mutant. M68T also colocalized with CD63‐positive vesicles in the endosomal–lysosomal system and was found to be more susceptible to lysosomal proteolysis than wild‐type ε‐sarcoglycan. Finally, we demonstrate impaired ectodomain shedding of M68T, a process that occurs physiologically for ε‐sarcoglycan resulting in the lysosomal trafficking of the intracellular C‐terminal domain of the protein. Our findings show that functional analysis of rare missense mutations can provide a mechanistic insight into the pathogenesis of MDS and the physiological role of ε‐sarcoglycan. Hum Mutat 32:1246–1258, 2011. ©2011 Wiley Periodicals, Inc.</div></front></TEI><affiliations><list><country><li>Italie</li><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Latium</li><li>Oxfordshire</li></region><settlement><li>Oxford</li><li>Rome</li></settlement><orgName><li>Université d'Oxford</li></orgName></list><tree><country name="Royaume-Uni"><noRegion><name sortKey="Waite, Adrian" sort="Waite, Adrian" uniqKey="Waite A" first="Adrian" last="Waite">Adrian Waite</name></noRegion><name sortKey="Blake, Derek J" sort="Blake, Derek J" uniqKey="Blake D" first="Derek J." last="Blake">Derek J. Blake</name><name sortKey="Blake, Derek J" sort="Blake, Derek J" uniqKey="Blake D" first="Derek J." last="Blake">Derek J. Blake</name><name sortKey="Blake, Derek J" sort="Blake, Derek J" uniqKey="Blake D" first="Derek J." last="Blake">Derek J. Blake</name><name sortKey="Waite, Adrian" sort="Waite, Adrian" uniqKey="Waite A" first="Adrian" last="Waite">Adrian Waite</name></country><country name="Italie"><region name="Latium"><name sortKey="De Rosa, Maria Cristina" sort="De Rosa, Maria Cristina" uniqKey="De Rosa M" first="Maria Cristina" last="De Rosa">Maria Cristina De Rosa</name></region><name sortKey="Brancaccio, Andrea" sort="Brancaccio, Andrea" uniqKey="Brancaccio A" first="Andrea" last="Brancaccio">Andrea Brancaccio</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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