A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia

Mencacci, N E and Rubio-Agusti, I and Zdebik, A and Asmus, F and Ludtmann, M H R and Ryten, M and Plagnol, V and Hauser, A K and Bandres-Ciga, S and Bettencourt, C and Forabosco, P and Hughes, D and Soutar, M M and Peall, K and Morris, H R and Trabzuni, D and Tekman, M and Stanescu, H C and Kleta, R and Carecchio, M and Zorzi, G and Nardocci, N and Garavaglia, B and Lohmann, E and Weissbach, A and Klein, C and Hardy, J and Pittman, A M and Foltynie, T and Abramov, A Y and Gasser, T and Bhatia, K P and Wood, N W (2015) A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia. American Journal of Human Genetics, 96 (6). pp. 938-47.

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Abstract

Myoclonus-dystonia (M-D) is a rare movement disorder characterized by a combination of non-epileptic myoclonic jerks and dystonia. SGCE mutations represent a major cause for familial M-D being responsible for 30%–50% of cases. After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c.434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family. The clinical presentation of the KCTD17-mutated cases was distinct from the phenotype usually observed in M-D due to SGCE mutations. All cases initially presented with mild myoclonus affecting the upper limbs. Dystonia showed a progressive course, with increasing severity of symptoms and spreading from the cranio-cervical region to other sites. KCTD17 is abundantly expressed in all brain regions with the highest expression in the putamen. Weighted gene co-expression network analysis, based on mRNA expression profile of brain samples from neuropathologically healthy individuals, showed that KCTD17 is part of a putamen gene network, which is significantly enriched for dystonia genes. Functional annotation of the network showed an over-representation of genes involved in post-synaptic dopaminergic transmission. Functional studies in mutation bearing fibroblasts demonstrated abnormalities in endoplasmic reticulum-dependent calcium signaling. In conclusion, we demonstrate that the KCTD17 c.434 G>A p.(Arg145His) mutation causes autosomal dominant M-D. Further functional studies are warranted to further characterize the nature of KCTD17 contribution to the molecular pathogenesis of M-D.