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

Eva Hebert,Katja Lohmann,Thomas Gasser,Michaela Müller,Susen Schaake,Beomseok Jeon,Humera Manzoor,Alexander Schmidt,Leopold Größer,Jennie Hampf,Ingrid Brænne,Meike Kasten,Eckart Altenmüller,Christine Klein,Friederike Borngräber,Aleksandar Raković ,Kirsten E Zeuner ,Anne Weißbach ,Daniel Alvarez‐Fischer ,Péter Bauer ,Vladimir Kostić ,Hans‐Christian Jabusch ,Eva Juliane Vollstedt ,Han Joon Kim

doi:10.3390/genes8100276

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.

Highlights

Musician’s dystonia (MD) is a task-specific movement disorder that is characterized by painless muscle incoordination or loss of voluntary motor control while the musician is playing the instrument [1,2].It occurs in professional instrumentalists with a prevalence of 1–2% [3]
Among 74 unrelated writer’s dystonia (WD) patients, we found another carrier of p.Ile196Val (L-9497) and two patients with another substitution (c.520G>A, p.Ala174Thr, L-11086, L-11092)
We here report an enrichment of rare missense variants in dystonia patients (12/919, 1.3%), in patients with musician’s dystonia (MD) (5/242, 2.1%) compared to healthy controls (1/461, 0.2%) and PD

Summary

Introduction

Musician’s dystonia (MD) is a task-specific movement disorder that is characterized by painless muscle incoordination or loss of voluntary motor control while the musician is playing the instrument [1,2]. It occurs in professional instrumentalists with a prevalence of 1–2% [3]. About 20% of MD patients report a positive family history, including MD or writer’s dystonia (WD) [4]. WD is another form of a task-specific dystonia involving the fingers, hand, and/or forearm. Symptoms usually appear when a person is trying to do a task that requires fine motor movements, such as writing.

Methods

Results

Conclusion