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A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia

Mencacci, N E; Rubio-Agusti, I; Zdebik, A; Asmus, F; Ludtmann, M H R; Ryten, M; Plagnol, V; Hauser, A K; Bandres-Ciga, S; Bettencourt, C; Forabosco, P; Hughes, D; Soutar, M M; Peall, K; Morris, H R; Trabzuni, D; Tekman, M; Stanescu, H C; Kleta, R; Carecchio, M; Zorzi, G; Nardocci, N; Garavaglia, B; Lohmann, E; Weissbach, A; Klein, C; Hardy, J; Pittman, A M; Foltynie, T; Abramov, A Y; Gasser, T; Bhatia, K P; Wood, N W


N E Mencacci

I Rubio-Agusti

A Zdebik

F Asmus

M H R Ludtmann

M Ryten

V Plagnol

A K Hauser

S Bandres-Ciga

C Bettencourt

P Forabosco

D Hughes

M M Soutar

K Peall

H R Morris

D Trabzuni

M Tekman

H C Stanescu

R Kleta

M Carecchio

G Zorzi

N Nardocci

B Garavaglia

E Lohmann

A Weissbach

C Klein

J Hardy

A M Pittman

T Foltynie

A Y Abramov

T Gasser

K P Bhatia

N 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.


Mencacci, N. E., Rubio-Agusti, I., Zdebik, A., Asmus, F., Ludtmann, M. H. R., Ryten, M., …Wood, N. W. (in press). A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia. American Journal of Human Genetics, 96(6), 938-47.

Journal Article Type Article
Acceptance Date Apr 13, 2015
Deposit Date Jul 24, 2018
Journal American Journal of Human Genetics
Print ISSN 0002-9297
Publisher Cell Press
Volume 96
Issue 6
Pages 938-47
Public URL

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