Novel <em>MAG</em> Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype
Homozygous variants in <i>MAG</i>, encoding myelin-associated glycoprotein (MAG), have been associated with complicated forms of hereditary spastic paraplegia (HSP). MAG is a glycoprotein member of the immunoglobulin superfamily, expressed by myelination cells. In this study, we identifi...
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MDPI AG
2020-04-01
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| Series: | Journal of Clinical Medicine |
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| Online Access: | https://www.mdpi.com/2077-0383/9/4/1212 |
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| author | Mariana Santos Joana Damásio Célia Kun-Rodrigues Clara Barbot Jorge Sequeiros José Brás Isabel Alonso Rita Guerreiro |
| author_facet | Mariana Santos Joana Damásio Célia Kun-Rodrigues Clara Barbot Jorge Sequeiros José Brás Isabel Alonso Rita Guerreiro |
| author_sort | Mariana Santos |
| collection | DOAJ |
| description | Homozygous variants in <i>MAG</i>, encoding myelin-associated glycoprotein (MAG), have been associated with complicated forms of hereditary spastic paraplegia (HSP). MAG is a glycoprotein member of the immunoglobulin superfamily, expressed by myelination cells. In this study, we identified a novel homozygous missense variant in <i>MAG</i> (c.124T>C; p.Cys42Arg) in a Portuguese family with early-onset autosomal recessive cerebellar ataxia with neuropathy and oculomotor apraxia. We used homozygosity mapping and exome sequencing to identify the <i>MAG</i> variant, and cellular studies to confirm its detrimental effect. Our results showed that this variant reduces protein stability and impairs the post-translational processing (N-linked glycosylation) and subcellular localization of MAG, thereby associating a loss of protein function with the phenotype. Therefore, <i>MAG</i> variants should be considered in the diagnosis of hereditary cerebellar ataxia with oculomotor apraxia, in addition to spastic paraplegia. |
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| institution | Directory Open Access Journal |
| issn | 2077-0383 |
| language | English |
| last_indexed | 2024-03-10T20:17:39Z |
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| spelling | doaj.art-b7cd60c20f564cefa2d63848b5941ddd2023-11-19T22:29:02ZengMDPI AGJournal of Clinical Medicine2077-03832020-04-0194121210.3390/jcm9041212Novel <em>MAG</em> Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical PhenotypeMariana Santos0Joana Damásio1Célia Kun-Rodrigues2Clara Barbot3Jorge Sequeiros4José Brás5Isabel Alonso6Rita Guerreiro7UnIGENe, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalUnIGENe, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalCenter for Neurodegenerative Science, Van Andel Institute, Grand Rapids, Michigan, MI 49503, USACGPP, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalUnIGENe, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalCenter for Neurodegenerative Science, Van Andel Institute, Grand Rapids, Michigan, MI 49503, USAUnIGENe, IBMC-Institute for Molecular and Cell Biology, i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, PortugalCenter for Neurodegenerative Science, Van Andel Institute, Grand Rapids, Michigan, MI 49503, USAHomozygous variants in <i>MAG</i>, encoding myelin-associated glycoprotein (MAG), have been associated with complicated forms of hereditary spastic paraplegia (HSP). MAG is a glycoprotein member of the immunoglobulin superfamily, expressed by myelination cells. In this study, we identified a novel homozygous missense variant in <i>MAG</i> (c.124T>C; p.Cys42Arg) in a Portuguese family with early-onset autosomal recessive cerebellar ataxia with neuropathy and oculomotor apraxia. We used homozygosity mapping and exome sequencing to identify the <i>MAG</i> variant, and cellular studies to confirm its detrimental effect. Our results showed that this variant reduces protein stability and impairs the post-translational processing (N-linked glycosylation) and subcellular localization of MAG, thereby associating a loss of protein function with the phenotype. Therefore, <i>MAG</i> variants should be considered in the diagnosis of hereditary cerebellar ataxia with oculomotor apraxia, in addition to spastic paraplegia.https://www.mdpi.com/2077-0383/9/4/1212cerebellar ataxiamyelin-associated glycoproteinexome sequencing |
| spellingShingle | Mariana Santos Joana Damásio Célia Kun-Rodrigues Clara Barbot Jorge Sequeiros José Brás Isabel Alonso Rita Guerreiro Novel <em>MAG</em> Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype Journal of Clinical Medicine cerebellar ataxia myelin-associated glycoprotein exome sequencing |
| title | Novel <em>MAG</em> Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype |
| title_full | Novel <em>MAG</em> Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype |
| title_fullStr | Novel <em>MAG</em> Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype |
| title_full_unstemmed | Novel <em>MAG</em> Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype |
| title_short | Novel <em>MAG</em> Variant Causes Cerebellar Ataxia with Oculomotor Apraxia: Molecular Basis and Expanded Clinical Phenotype |
| title_sort | novel em mag em variant causes cerebellar ataxia with oculomotor apraxia molecular basis and expanded clinical phenotype |
| topic | cerebellar ataxia myelin-associated glycoprotein exome sequencing |
| url | https://www.mdpi.com/2077-0383/9/4/1212 |
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