Genes (Basel). 2017 Oct 18;8(10). pii: E276. doi: 10.3390/genes8100276.

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

Hebert E¹, Borngräber F^2,^3,⁴, Schmidt A^5,^6,⁷, Rakovic A⁸, Brænne I⁹, Weissbach A¹⁰, Hampf J¹¹, Vollstedt EJ¹², Größer L¹³, Schaake S¹⁴, Müller M¹⁵, Manzoor H^16,¹⁷, Jabusch HC¹⁸, Alvarez-Fischer D¹⁹, Kasten M^20,²¹, Kostic VS²², Gasser T²³, Zeuner KE²⁴, Kim HJ²⁵, Jeon B²⁶, Bauer P²⁷, Altenmüller E²⁸, Klein C²⁹, Lohmann K³⁰.

Author information

1: Institute of Neurogenetics, University of Luebeck, 23538 Luebeck, Germany. eva.hebert@neuro.uni-luebeck.de.
2: Institute of Neurogenetics, University of Luebeck, 23538 Luebeck, Germany. friederike.borngraeber@neuro.uni-luebeck.de.
3: Kurt Singer Institute for Music Physiology and Musicians' Health, Hanns Eisler School of Music Berlin, 10595 Berlin, Germany. friederike.borngraeber@neuro.uni-luebeck.de.
4: Berlin Center for Musicians' Medicine, Charité-University Medicine Berlin, 10117 Berlin, Germany. friederike.borngraeber@neuro.uni-luebeck.de.
5: Institute of Neurogenetics, University of Luebeck, 23538 Luebeck, Germany. alexander.schmidt@charite.de.
6: Kurt Singer Institute for Music Physiology and Musicians' Health, Hanns Eisler School of Music Berlin, 10595 Berlin, Germany. alexander.schmidt@charite.de.
7: Berlin Center for Musicians' Medicine, Charité-University Medicine Berlin, 10117 Berlin, Germany. alexander.schmidt@charite.de.
8: Institute of Neurogenetics, University of Luebeck, 23538 Luebeck, Germany. aleksandar.rakovic@neuro.uni-luebeck.de.
9: Institute for Integrative and Experimental Genomics, University of Luebeck, 23538 Luebeck, Germany. imb9y@eservices.virginia.edu.
10: Institute of Neurogenetics, University of Luebeck, 23538 Luebeck, Germany. anne.weissbach@neuro.uni-luebeck.de.
11: Institute of Neurogenetics, University of Luebeck, 23538 Luebeck, Germany. jennie.hampf@neuro.uni-luebeck.de.
12: Institute of Neurogenetics, University of Luebeck, 23538 Luebeck, Germany. jule.vollstedt@neuro.uni-luebeck.de.
13: Department of Dermatology, University of Regensburg, 93053 Regensburg, Germany. Leopold.Groesser@klinik.uni-regensburg.de.
14: Institute of Neurogenetics, University of Luebeck, 23538 Luebeck, Germany. susen.schaake@neuro.uni-luebeck.de.
15: Institute for Integrative and Experimental Genomics, University of Luebeck, 23538 Luebeck, Germany. michaela.mueller@iieg.uni-luebeck.de.
16: Institute of Neurogenetics, University of Luebeck, 23538 Luebeck, Germany. humi_902@yahoo.com.
17: School of Biological Sciences, University of the Punjab, Quaid-i-Azam Campus, Lahore 54590, Pakistan. humi_902@yahoo.com.
18: Institute of Musician's Medicine, University of Music, 01069 Dresden, Germany. Hans-Christian.Jabusch@hfmdd.de.
19: Institute of Neurogenetics, University of Luebeck, 23538 Luebeck, Germany. daniel.alvarez@neuro.uni-luebeck.de.
20: Institute of Neurogenetics, University of Luebeck, 23538 Luebeck, Germany. meike.kasten@neuro.uni-luebeck.de.
21: Department of Psychiatry and Psychotherapy, University of Lübeck, 23538 Lubeck, Germany. meike.kasten@neuro.uni-luebeck.de.
22: Department of Neurodegenerative Diseases, Clinical Center of Serbia, 11000 Belgrade, Serbia. vladimir.s.kostic@gmail.com.
23: Department of Neurology, University of Tübingen, 72076 Tubingen, Germany. thomas.gasser@uni-tuebingen.de.
24: Department of Neurology, University of Kiel, 24105 Kiel, Germany. k.zeuner@neurologie.uni-kiel.de.
25: Department of Neurology, Movement Disorder Center, Seoul National University Hospital, Seoul 03080, Korea. cupofcoffee@daum.net.
26: Department of Neurology, Movement Disorder Center, Seoul National University Hospital, Seoul 03080, Korea. brain@snu.ac.kr.
27: Centogene AG, 18057 Rostock, Germany. peter.bauer@centogene.com.
28: Institute of Music Physiology and Musician's Medicine, Hanover University of Music, Drama and Media, 30175 Hanover, Germany. eckart.altenmueller@hmtm-hannover.de.
29: Institute of Neurogenetics, University of Luebeck, 23538 Luebeck, Germany. christine.klein@neuro.uni-luebeck.de.
30: Institute of Neurogenetics, University of Luebeck, 23538 Luebeck, Germany. katja.lohmann@neuro.uni-luebeck.de.

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.

KEYWORDS:

GTPase; RAB12; Transferrin receptor; lysosomal degradation; musician’s dystonia

PMID:: 29057844
PMCID:: PMC5664126
DOI:: 10.3390/genes8100276

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Conflict of interest statement

The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.