Helbig KL et al. (2016), A recurrent mutation in KCNA2 as a novel cause ...

XB-ART-52363

Ann Neurol 2016 Oct 01;804:. doi: 10.1002/ana.24762.

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A recurrent mutation in KCNA2 as a novel cause of hereditary spastic paraplegia and ataxia.

Helbig KL, Hedrich UB, Shinde DN, Krey I, Teichmann AC, Hentschel J, Schubert J, Chamberlin AC, Huether R, Lu HM, Alcaraz WA, Tang S, Jungbluth C, Dugan SL, Vainionpää L, Karle KN, Synofzik M, Schöls L, Schüle R, Lehesjoki AE, Helbig I, Lerche H, Lemke JR.

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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, KV 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 KV 1.2 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. Ann Neurol 2016.

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Species referenced: Xenopus laevis
Genes referenced: kcna2

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Figure 1. (A) Structure of the voltage‐gated potassium channel, Kv1.2, with transmembrane segments S1 to S4 forming the voltage sensor domain (light gray) and segments S5 and S6 forming the pore region (dark gray) with its pore‐forming loop and location of p.R294H mutation, within transmembrane segment S4, which constitutes the voltage sensor. (B) Evolutionary conservation of R294 amino acid residue and neighboring R297 and L298, which have been implicated in epileptic encephalopathies. (C) Pedigrees of all three families with identified p.R294H mutations along with cosegregation data. WT = wild type. [Color figure can be viewed in the online issue, which is available at www.annalsofneurology.org.]

Figure 2. Functional effects of the p.R294H KCNA2 mutation. (A) Recordings of currents elicited by increasing voltage steps from a holding potential of –80mV from Xenopus laevis oocytes expressing either WT KV1.2 channels (left), R294H mutant channels (center), or both (right). (B) Amplitudes of recorded currents normalized to the mean current amplitude of the WT. Amplitudes decreased with increasing amounts of injected mutant cRNA, whereas the amount of WT cRNA remained constant, suggesting a dominant‐negative effect on WT channels. Groups were statistically different (one‐way ANOVA: p < 0.001; post‐hoc Dunn's method: p < 0.05). Shown are means ± SEM. (C) Activation curves of WT, R294H mutant, and a 1:1 expression of both clones, showing a significantly different shift to more‐depolarized potentials for mutant channels, consistent with a loss‐of‐channel function (one‐way ANOVA: p < 0.001; post‐hoc Dunn's method: p < 0.05). Shown are means ± SEM. Lines represent Boltzmann functions fit to data points. ANOVA = analysis of variance; cRNA = complementary RNA; SEM = standard error of the mean; WT = wild type. [Color figure can be viewed in the online issue, which is available at www.annalsofneurology.org.]

References [+] :

Aggarwal, Contribution of the S4 segment to gating charge in the Shaker K+ channel. 1996, Pubmed, Xenbase