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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 938-947 |
| Number of pages | 10 |
| Journal | American journal of human genetics |
| Volume | 96 |
| Issue number | 6 |
| DOIs | |
| State | Published - May 1 2015 |
Funding
We would like to extend our thanks to the individuals whose participation made this research possible. This work was supported financially by a Medical Research Council/Wellcome Trust Strategic Award (WT089698/Z/09/Z) and a grant from the Bachman-Strauss Dystonia Parkinsonism Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The work was undertaken at University College London Hospitals (UCLH) and University College London (UCL), who receive support from the Department of Health’s NIHR Biomedical Research Center’s funding streams. E.L. and T.G. are supported by a grant from the Dystonia Medical Research Foundation (DMRF). C.K. is the recipient of a career development award from the Herman and Lilly Schilling Foundation. A.M.P. is funded by the Reta Lila Weston Trust. S.B.C. held a FPU fellowship from the Spanish Ministry of Education and Science jointly with a short-term stay grant by Cei-BioTic and University of Granada. Next Generation Sequencing was performed at the UCL Institute of Neurology Sequencing Facility. We thank the UCL-Exomes Consortium for providing the exome sequencing data of UK population controls. Expression data was provided by the UK Human Brain Expression Consortium (UKBEC), which comprises J.H., M.R., Michael Weale, D.T., Adaikalavan Ramasamy, Colin Smith, and Robert Walker. UKBEC members are affiliated with UCL Institute of Neurology (J.H., M.R., D.T.), King’s College London (M.R., Adaikalavan Ramasamy, and Michael Weale), and the University of Edinburgh (Colin Smith and Robert Walker). We thank Miss Elisavet Preza for providing help with the skin biopsy preparation.
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)