A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia

Niccolo E. Mencacci, Ignacio Rubio-Agusti, Anselm Zdebik, Friedrich Asmus, Marthe H.R. Ludtmann, Mina Ryten, Vincent Plagnol, Ann-Kathrin Hauser, Sara Bandres-Ciga, Conceição Bettencourt, Paola Forabosco, Deborah Hughes, Marc M.P. Soutar, Kathryn Peall, Huw R. Morris, Daniah Trabzuni, Mehmet Tekman, Horia C. Stanescu, Robert Kleta, Miryam Carecchio, Giovanna Zorzi, Nardo Nardocci, Barbara Garavaglia, Ebba Lohmann, Anne Weissbach, Christine Klein, John Hardy, Alan M. Pittman, Thomas Foltynie, Andrey Y. Abramov, Thomas Gasser, Kailash P. Bhatia, Nicholas W. Wood

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.