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Genes 2017, 8(10), 276; doi:10.3390/genes8100276

Functional Characterization of Rare RAB12 Variants and Their Role in Musician’s and Other Dystonias

1
Institute of Neurogenetics, University of Luebeck, 23538 Luebeck, Germany
2
Kurt Singer Institute for Music Physiology and Musicians’ Health, Hanns Eisler School of Music Berlin, 10595 Berlin, Germany
3
Berlin Center for Musicians’ Medicine, Charité—University Medicine Berlin, 10117 Berlin, Germany
4
Institute for Integrative and Experimental Genomics, University of Luebeck, 23538 Luebeck, Germany
5
Department of Dermatology, University of Regensburg, 93053 Regensburg, Germany
6
School of Biological Sciences, University of the Punjab, Quaid-i-Azam Campus, Lahore 54590, Pakistan
7
Institute of Musician’s Medicine, University of Music, 01069 Dresden, Germany
8
Department of Psychiatry and Psychotherapy, University of Lübeck, 23538 Lubeck, Germany
9
Department of Neurodegenerative Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia
10
Department of Neurology, University of Tübingen, 72076 Tubingen, Germany
11
Department of Neurology, University of Kiel, 24105 Kiel, Germany
12
Department of Neurology, Movement Disorder Center, Seoul National University Hospital, Seoul 03080, Korea
13
Centogene AG, 18057 Rostock, Germany
14
Institute of Music Physiology and Musician’s Medicine, Hanover University of Music, Drama and Media, 30175 Hanover, Germany
These two authors contributed equally to this study.
*
Author to whom correspondence should be addressed.
Academic Editor: Dale R. Nyholt
Received: 13 September 2017 / Revised: 16 October 2017 / Accepted: 17 October 2017 / Published: 18 October 2017
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Abstract

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. View Full-Text
Keywords: musician’s dystonia; RAB12; GTPase; Transferrin receptor; lysosomal degradation musician’s dystonia; RAB12; GTPase; Transferrin receptor; lysosomal degradation
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MDPI and ACS Style

Hebert, E.; Borngräber, F.; Schmidt, A.; Rakovic, A.; Brænne, I.; Weissbach, A.; Hampf, J.; Vollstedt, E.-J.; Größer, L.; Schaake, S.; Müller, M.; Manzoor, H.; Jabusch, H.-C.; Alvarez-Fischer, D.; Kasten, M.; Kostic, V.S.; Gasser, T.; Zeuner, K.E.; Kim, H.-J.; Jeon, B.; Bauer, P.; Altenmüller, E.; Klein, C.; Lohmann, K. Functional Characterization of Rare RAB12 Variants and Their Role in Musician’s and Other Dystonias. Genes 2017, 8, 276.

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