Objective: To evaluate the role of mutations in RAB12 in different forms of dystonia.

Background: By next generation sequencing, we recently identified an extremely rare missense variant (Ile196Val) in RAB12 in two of three small families with musician’s dystonia (MD) and writer’s dystonia (WD). While MD and WD are task-specific movement disorders, other dystonias persistently affect postures as in the case of cervical dystonia. RAB12 encodes a small GTPase which regulates the degradation of transmembrane proteins including the transferrin receptor 1 (TFRC).

Methods: We performed Sanger sequencing of RAB12 in 814 additional dystonia patients, 333 Parkinson´s disease patients, and 461 healthy controls. Functional characterization of two RAB12 variants (Ile196Val, Gly13Asp) was performed using patient-derived fibroblasts and two RAB12-overexpressing cell models.

Results: We identified 4 additional carriers of rare, missense changes among dystonia patients (0.5%) but only one carrier among the non-dystonia individuals (0.1%). The detected variants comprised Gly13Asp, Ala148Thr, Arg181Gln, and Ile196Val and were found in patients with MD, WD, and cervical dystonia. Of note, the Ile196Val mutation has previously also been found in two families with MD/WD. RAB12 is a gene with only about 50 reported missense variants in the about 60,000 exomes of the Exome Aggreggation Consortium (ExAC). Functional characterization revealed increased GTPase activity in mutants compared to wildtype. Further, subcellular distribution of RAB12 and lysosomes in mutants were altered in fibroblasts. Soluble Transferrin receptor 1 levels were reduced in blood of all three tested Ile196Val carriers.

Conclusions: Our data suggest a role of RAB12 variants in the etiology of MD and other dystonias.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rab12-variants-and-their-role-in-dystonia/