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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MDPI AG
2017-10-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/8/10/276 |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Eva Hebert Friederike Borngräber Alexander Schmidt Aleksandar Rakovic Ingrid Brænne Anne Weissbach Jennie Hampf Eva-Juliane Vollstedt Leopold Größer Susen Schaake Michaela Müller Humera Manzoor Hans-Christian Jabusch Daniel Alvarez-Fischer Meike Kasten Vladimir S. Kostic Thomas Gasser Kirsten E. Zeuner Han-Joon Kim Beomseok Jeon Peter Bauer Eckart Altenmüller Christine Klein Katja Lohmann |
| spellingShingle |
Eva Hebert Friederike Borngräber Alexander Schmidt Aleksandar Rakovic Ingrid Brænne Anne Weissbach Jennie Hampf Eva-Juliane Vollstedt Leopold Größer Susen Schaake Michaela Müller Humera Manzoor Hans-Christian Jabusch Daniel Alvarez-Fischer Meike Kasten Vladimir S. Kostic Thomas Gasser Kirsten E. Zeuner Han-Joon Kim Beomseok Jeon Peter Bauer Eckart Altenmüller Christine Klein Katja Lohmann Functional Characterization of Rare RAB12 Variants and Their Role in Musician’s and Other Dystonias Genes musician’s dystonia RAB12 GTPase Transferrin receptor lysosomal degradation |
| author_facet |
Eva Hebert Friederike Borngräber Alexander Schmidt Aleksandar Rakovic Ingrid Brænne Anne Weissbach Jennie Hampf Eva-Juliane Vollstedt Leopold Größer Susen Schaake Michaela Müller Humera Manzoor Hans-Christian Jabusch Daniel Alvarez-Fischer Meike Kasten Vladimir S. Kostic Thomas Gasser Kirsten E. Zeuner Han-Joon Kim Beomseok Jeon Peter Bauer Eckart Altenmüller Christine Klein Katja Lohmann |
| author_sort |
Eva Hebert |
| title |
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_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_sort |
functional characterization of rare rab12 variants and their role in musician’s and other dystonias |
| publisher |
MDPI AG |
| series |
Genes |
| issn |
2073-4425 |
| publishDate |
2017-10-01 |
| 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. |
| topic |
musician’s dystonia RAB12 GTPase Transferrin receptor lysosomal degradation |
| url |
https://www.mdpi.com/2073-4425/8/10/276 |
| work_keys_str_mv |
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doaj-68ef966d001943d7bf13279faa7f2f2c2020-11-24T23:03:48ZengMDPI AGGenes2073-44252017-10-0181027610.3390/genes8100276genes8100276Functional Characterization of Rare RAB12 Variants and Their Role in Musician’s and Other DystoniasEva Hebert0Friederike Borngräber1Alexander Schmidt2Aleksandar Rakovic3Ingrid Brænne4Anne Weissbach5Jennie Hampf6Eva-Juliane Vollstedt7Leopold Größer8Susen Schaake9Michaela Müller10Humera Manzoor11Hans-Christian Jabusch12Daniel Alvarez-Fischer13Meike Kasten14Vladimir S. Kostic15Thomas Gasser16Kirsten E. Zeuner17Han-Joon Kim18Beomseok Jeon19Peter Bauer20Eckart Altenmüller21Christine Klein22Katja Lohmann23Institute of Neurogenetics, University of Luebeck, 23538 Luebeck, GermanyInstitute of Neurogenetics, University of Luebeck, 23538 Luebeck, GermanyInstitute of Neurogenetics, University of Luebeck, 23538 Luebeck, GermanyInstitute of Neurogenetics, University of Luebeck, 23538 Luebeck, GermanyInstitute for Integrative and Experimental Genomics, University of Luebeck, 23538 Luebeck, GermanyInstitute of Neurogenetics, University of Luebeck, 23538 Luebeck, GermanyInstitute of Neurogenetics, University of Luebeck, 23538 Luebeck, GermanyInstitute of Neurogenetics, University of Luebeck, 23538 Luebeck, GermanyDepartment of Dermatology, University of Regensburg, 93053 Regensburg, GermanyInstitute of Neurogenetics, University of Luebeck, 23538 Luebeck, GermanyInstitute for Integrative and Experimental Genomics, University of Luebeck, 23538 Luebeck, GermanyInstitute of Neurogenetics, University of Luebeck, 23538 Luebeck, GermanyInstitute of Musician’s Medicine, University of Music, 01069 Dresden, GermanyInstitute of Neurogenetics, University of Luebeck, 23538 Luebeck, GermanyInstitute of Neurogenetics, University of Luebeck, 23538 Luebeck, GermanyDepartment of Neurodegenerative Diseases, Clinical Center of Serbia, 11000 Belgrade, SerbiaDepartment of Neurology, University of Tübingen, 72076 Tubingen, GermanyDepartment of Neurology, University of Kiel, 24105 Kiel, GermanyDepartment of Neurology, Movement Disorder Center, Seoul National University Hospital, Seoul 03080, KoreaDepartment of Neurology, Movement Disorder Center, Seoul National University Hospital, Seoul 03080, KoreaCentogene AG, 18057 Rostock, GermanyInstitute of Music Physiology and Musician’s Medicine, Hanover University of Music, Drama and Media, 30175 Hanover, GermanyInstitute of Neurogenetics, University of Luebeck, 23538 Luebeck, GermanyInstitute of Neurogenetics, University of Luebeck, 23538 Luebeck, GermanyMutations 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.https://www.mdpi.com/2073-4425/8/10/276musician’s dystoniaRAB12GTPaseTransferrin receptorlysosomal degradation |