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A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.
- Source :
-
Nature genetics [Nat Genet] 2015 Jan; Vol. 47 (1), pp. 39-46. Date of Electronic Publication: 2014 Nov 17. - Publication Year :
- 2015
-
Abstract
- Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31%). Remarkably, a recurrent de novo mutation, c.959G>A (p.Arg320His), in KCNC1 was identified as a new major cause for PME. Eleven unrelated exome-sequenced (13%) and two affected individuals in a secondary cohort (7%) had this mutation. KCNC1 encodes KV3.1, a subunit of the KV3 voltage-gated potassium ion channels, which are major determinants of high-frequency neuronal firing. Functional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect. Ten cases had pathogenic mutations in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6 and SERPINI1). Identification of mutations in PRNP, SACS and TBC1D24 expand their phenotypic spectra to PME. These findings provide insights into the molecular genetic basis of PME and show the role of de novo mutations in this disease entity.
- Subjects :
- Amino Acid Sequence
Amino Acid Substitution
Animals
Base Sequence
Carrier Proteins genetics
Conserved Sequence
Exome
Female
GTPase-Activating Proteins
Genes, Dominant
Heat-Shock Proteins genetics
Humans
Male
Membrane Proteins
Molecular Sequence Data
Nerve Tissue Proteins
Pedigree
Prion Proteins
Prions genetics
Protein Conformation
Sequence Alignment
Sequence Homology, Amino Acid
Shaw Potassium Channels physiology
Species Specificity
Mutation, Missense
Myoclonic Epilepsies, Progressive genetics
Point Mutation
Shaw Potassium Channels genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1718
- Volume :
- 47
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature genetics
- Publication Type :
- Academic Journal
- Accession number :
- 25401298
- Full Text :
- https://doi.org/10.1038/ng.3144