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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
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.
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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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