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A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia
Autors de IIS La Fe
Autors aliens a IIS La Fe
- Mencacci, NE
- Zdebik, A
- Asmus, F
- Ludtmann, MHR
- Ryten, M
- Plagnol, V
- Hauser, AK
- Bandres-Ciga, S
- Bettencourt, C
- Forabosco, P
- Hughes, D
- Soutar, MMP
- Peall, K
- Morris, HR
- Trabzuni, D
- Tekman, M
- Stanescu, HC
- Kleta, R
- Carecchio, M
- Zorzi, G
- Nardocci, N
- Garavaglia, B
- Lohmann, E
- Weissbach, A
- Klein, C
- Hardy, J
- Pittman, AM
- Foltynie, T
- Abramov, AY
- Gasser, T
- Bhatia, KP
- Wood, NW
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.
Dades de la publicació
- ISSN/ISSNe:
- 0002-9297, 1537-6605
- Tipus:
- Article
- Pàgines:
- 938-947
- PubMed:
- 25983243
- Factor d'Impacte:
- 8,755 SCImago ℠
- Quartil:
- Q1 SCImago ℠
AMERICAN JOURNAL OF HUMAN GENETICS CELL PRESS
Cites Rebudes en Web of Science: 78
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