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A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia
- Source :
- AMERICAN JOURNAL OF HUMAN GENETICS, r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe, instname, The American journal of human genetics 96(6), 938-947 (2015). doi:10.1016/j.ajhg.2015.04.008
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
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.
- Subjects :
- genetics [Dystonic Disorders]
genetics [Synaptic Transmission]
Male
Potassium Channels
genetics [Mutation, Missense]
Molecular Sequence Data
pathology [Dystonic Disorders]
Mutation, Missense
Synaptic Transmission
ddc:570
genetics [Adaptor Proteins, Signal Transducing]
Germany
Report
genetics [Genes, Dominant]
genetics [Exome]
Genetics
metabolism [Dystonic Disorders]
Humans
Exome
Gene Regulatory Networks
Genetics(clinical)
Adaptor Proteins, Signal Transducing
Genes, Dominant
Base Sequence
genetics [Potassium Channels]
Brain
Chromosome Mapping
Sequence Analysis, DNA
KCTD17 protein, human
United Kingdom
Pedigree
metabolism [Brain]
Dystonic Disorders
genetics [Gene Regulatory Networks]
Female
Subjects
Details
- ISSN :
- 00029297
- Volume :
- 96
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- The American Journal of Human Genetics
- Accession number :
- edsair.pmid.dedup....24661a39fc086395842a819625c39e51
- Full Text :
- https://doi.org/10.1016/j.ajhg.2015.04.008