期刊
ANNALS OF NEUROLOGY
卷 80, 期 4, 页码 638-642出版社
WILEY-BLACKWELL
DOI: 10.1002/ana.24762
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资金
- Else Kroner-Fresenius-Stiftung [EKMS 018]
- European Union for the NEUROMICS network [F5-2012-305121]
- Folkhalsan Research Foundation
- Academy of Finland [141549]
- University of Kiel
- German Research Foundation (DFG) within the EuroEPINOMICS framework of the European Science Foundation [HE5415/3-1]
- DFG [HE5415/5-1, HE 5415/6-1, Le1030/10-2, Le1030/11-1]
- German Ministry for Education and Research [01DH12033, MAR 10/012]
- German chapter of the International League against Epilepsy (DGfE)
- Children's Hospital of Philadelphia (CHOP)
- Genomics Research Initiative Network (GRIN)
- International League Against Epilepsy (ILAE) within the Epilepsiome initiative of the ILAE Genetics Commission
- EuroEPINOMICS network of the European Science Foundation
- German network for rare diseases of the BMBF (IonNeurONet) [01GM1105A]
- Academy of Finland (AKA) [141549, 141549] Funding Source: Academy of Finland (AKA)
The hereditary spastic paraplegias (HSPs) are heterogeneous neurodegenerative disorders with over 50 known causative genes. We identified a recurrent mutation in KCNA2 (c.881G>A, p.R294H), encoding the voltage-gated K+-channel, K(V)1.2, in two unrelated families with HSP, intellectual disability (ID), and ataxia. Follow-up analysis of >2,000 patients with various neurological phenotypes identified a de novo p.R294H mutation in a proband with ataxia and ID. Two-electrode voltage-clamp recordings of Xenopus laevis oocytes expressing mutant KV1.2 channels showed loss of function with a dominant-negative effect. Our findings highlight the phenotypic spectrum of a recurrent KCNA2 mutation, implicating ion channel dysfunction as a novel HSP disease mechanism.
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