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Functional Characterization of Rare RAB12 Variants and Their Role in Musician’s and Other Dystonias
Mutations in RAB (member of the Ras superfamily) genes are increasingly recognized as cause of a variety of disorders including neurological conditions. While musician’s dystonia (MD) and writer’s dystonia (WD) are task-specific movement disorders, other dystonias persistently affect postures as in...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664126/ https://www.ncbi.nlm.nih.gov/pubmed/29057844 http://dx.doi.org/10.3390/genes8100276 |
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author | Hebert, Eva Borngräber, Friederike Schmidt, Alexander Rakovic, Aleksandar Brænne, Ingrid Weissbach, Anne Hampf, Jennie Vollstedt, Eva-Juliane Größer, Leopold Schaake, Susen Müller, Michaela Manzoor, Humera Jabusch, Hans-Christian Alvarez-Fischer, Daniel Kasten, Meike Kostic, Vladimir S. Gasser, Thomas Zeuner, Kirsten E. Kim, Han-Joon Jeon, Beomseok Bauer, Peter Altenmüller, Eckart Klein, Christine Lohmann, Katja |
author_facet | Hebert, Eva Borngräber, Friederike Schmidt, Alexander Rakovic, Aleksandar Brænne, Ingrid Weissbach, Anne Hampf, Jennie Vollstedt, Eva-Juliane Größer, Leopold Schaake, Susen Müller, Michaela Manzoor, Humera Jabusch, Hans-Christian Alvarez-Fischer, Daniel Kasten, Meike Kostic, Vladimir S. Gasser, Thomas Zeuner, Kirsten E. Kim, Han-Joon Jeon, Beomseok Bauer, Peter Altenmüller, Eckart Klein, Christine Lohmann, Katja |
author_sort | Hebert, Eva |
collection | PubMed |
description | Mutations in RAB (member of the Ras superfamily) genes are increasingly recognized as cause of a variety of disorders including neurological conditions. While musician’s dystonia (MD) and writer’s dystonia (WD) are task-specific movement disorders, other dystonias persistently affect postures as in cervical dystonia. Little is known about the underlying etiology. Next-generation sequencing revealed a rare missense variant (c.586A>G; p.Ile196Val) in RAB12 in two of three MD/WD families. Next, we tested 916 additional dystonia patients; 512 Parkinson’s disease patients; and 461 healthy controls for RAB12 variants and identified 10 additional carriers of rare missense changes among dystonia patients (1.1%) but only one carrier in non-dystonic individuals (0.1%; p = 0.005). The detected variants among index patients comprised p.Ile196Val (n = 6); p.Ala174Thr (n = 3); p.Gly13Asp; p.Ala148Thr; and p.Arg181Gln in patients with MD; cervical dystonia; or WD. Two relatives of MD patients with WD also carried p.Ile196Val. The two variants identified in MD patients (p.Ile196Val; p.Gly13Asp) were characterized on endogenous levels in patient-derived fibroblasts and in two RAB12-overexpressing cell models. The ability to hydrolyze guanosine triphosphate (GTP), so called GTPase activity, was increased in mutants compared to wildtype. Furthermore, subcellular distribution of RAB12 in mutants was altered in fibroblasts. Soluble Transferrin receptor 1 levels were reduced in the blood of all three tested p.Ile196Val carriers. In conclusion, we demonstrate an enrichment of missense changes among dystonia patients. Functional characterization revealed altered enzyme activity and lysosomal distribution in mutants suggesting a contribution of RAB12 variants to MD and other dystonias. |
format | Online Article Text |
id | pubmed-5664126 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-56641262017-11-06 Functional Characterization of Rare RAB12 Variants and Their Role in Musician’s and Other Dystonias Hebert, Eva Borngräber, Friederike Schmidt, Alexander Rakovic, Aleksandar Brænne, Ingrid Weissbach, Anne Hampf, Jennie Vollstedt, Eva-Juliane Größer, Leopold Schaake, Susen Müller, Michaela Manzoor, Humera Jabusch, Hans-Christian Alvarez-Fischer, Daniel Kasten, Meike Kostic, Vladimir S. Gasser, Thomas Zeuner, Kirsten E. Kim, Han-Joon Jeon, Beomseok Bauer, Peter Altenmüller, Eckart Klein, Christine Lohmann, Katja Genes (Basel) Review Mutations in RAB (member of the Ras superfamily) genes are increasingly recognized as cause of a variety of disorders including neurological conditions. While musician’s dystonia (MD) and writer’s dystonia (WD) are task-specific movement disorders, other dystonias persistently affect postures as in cervical dystonia. Little is known about the underlying etiology. Next-generation sequencing revealed a rare missense variant (c.586A>G; p.Ile196Val) in RAB12 in two of three MD/WD families. Next, we tested 916 additional dystonia patients; 512 Parkinson’s disease patients; and 461 healthy controls for RAB12 variants and identified 10 additional carriers of rare missense changes among dystonia patients (1.1%) but only one carrier in non-dystonic individuals (0.1%; p = 0.005). The detected variants among index patients comprised p.Ile196Val (n = 6); p.Ala174Thr (n = 3); p.Gly13Asp; p.Ala148Thr; and p.Arg181Gln in patients with MD; cervical dystonia; or WD. Two relatives of MD patients with WD also carried p.Ile196Val. The two variants identified in MD patients (p.Ile196Val; p.Gly13Asp) were characterized on endogenous levels in patient-derived fibroblasts and in two RAB12-overexpressing cell models. The ability to hydrolyze guanosine triphosphate (GTP), so called GTPase activity, was increased in mutants compared to wildtype. Furthermore, subcellular distribution of RAB12 in mutants was altered in fibroblasts. Soluble Transferrin receptor 1 levels were reduced in the blood of all three tested p.Ile196Val carriers. In conclusion, we demonstrate an enrichment of missense changes among dystonia patients. Functional characterization revealed altered enzyme activity and lysosomal distribution in mutants suggesting a contribution of RAB12 variants to MD and other dystonias. MDPI 2017-10-18 /pmc/articles/PMC5664126/ /pubmed/29057844 http://dx.doi.org/10.3390/genes8100276 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Hebert, Eva Borngräber, Friederike Schmidt, Alexander Rakovic, Aleksandar Brænne, Ingrid Weissbach, Anne Hampf, Jennie Vollstedt, Eva-Juliane Größer, Leopold Schaake, Susen Müller, Michaela Manzoor, Humera Jabusch, Hans-Christian Alvarez-Fischer, Daniel Kasten, Meike Kostic, Vladimir S. Gasser, Thomas Zeuner, Kirsten E. Kim, Han-Joon Jeon, Beomseok Bauer, Peter Altenmüller, Eckart Klein, Christine Lohmann, Katja Functional Characterization of Rare RAB12 Variants and Their Role in Musician’s and Other Dystonias |
title | Functional Characterization of Rare RAB12 Variants and Their Role in Musician’s and Other Dystonias |
title_full | Functional Characterization of Rare RAB12 Variants and Their Role in Musician’s and Other Dystonias |
title_fullStr | Functional Characterization of Rare RAB12 Variants and Their Role in Musician’s and Other Dystonias |
title_full_unstemmed | Functional Characterization of Rare RAB12 Variants and Their Role in Musician’s and Other Dystonias |
title_short | Functional Characterization of Rare RAB12 Variants and Their Role in Musician’s and Other Dystonias |
title_sort | functional characterization of rare rab12 variants and their role in musician’s and other dystonias |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664126/ https://www.ncbi.nlm.nih.gov/pubmed/29057844 http://dx.doi.org/10.3390/genes8100276 |
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