Hebert, Eva and Borngraeber, Friederike and Schmidt, Alexander and Rakovic, Aleksandar and Braenne, Ingrid and Weissbach, Anne and Hampf, Jennie and Vollstedt, Eva-Juliane and Groesser, Leopold and Schaake, Susen and Mueller, Michaela and Manzoor, Humera and Jabusch, Hans-Christian and Alvarez-Fischer, Daniel and Kasten, Meike and Kostic, Vladimir S. and Gasser, Thomas and Zeuner, Kirsten E. and Kim, Han-Joon and Jeon, Beomseok and Bauer, Peter and Altenmueller, Eckart and Klein, Christine and Lohmann, Katja (2017) Functional Characterization of Rare RAB12 Variants and Their Role in Musician's and Other Dystonias. GENES, 8 (10): 276. ISSN 2073-4425
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SMALL GTPASE RAB12; FOCAL DYSTONIA; TRANSFERRIN RECEPTOR; MOVEMENT-DISORDERS; TRIGGERING FACTORS; IRON-METABOLISM; MUTATIONS; PROTEIN; PATHOPHYSIOLOGY; PHENOMENOLOGY; musician's dystonia; RAB12; GTPase; Transferrin receptor; lysosomal degradation |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Dermatologie und Venerologie |
| Depositing User: | Petra Gürster |
| Date Deposited: | 14 Dec 2018 13:19 |
| Last Modified: | 04 Sep 2020 08:02 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2055 |
Actions (login required)
 |
View Item |
