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

Abstract

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, KV1.2, 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. Ann Neurol 2016

The sigma‐1 receptor behaves as an atypical auxiliary subunit to modulate the functional characteristics of Kv1.2 channels expressed in HEK293 cells

“…; Robbins and Tempel ; Helbig et al. ). Therefore, in our final line of experimentation, we examined how modulation of Kv1.2 may be altered in cells expressing the mutant Sig‐1R underlying ALS16 (Sig‐1R‐E102Q; Al‐Saif et al.…”

“…A recurrent “loss‐of‐function” mutation in KCNA2 was recently identified which results in hereditary spastic paraplegia (Helbig et al. ). Hyperexcitability has also been observed in amyotrophic lateral sclerosis (ALS) patients (Nakata et al.…”

“…Mutations in the Sig-1R are clinically associated with motor neuron pathologies such as distal hereditary motor neuropathy and amyotrophic lateral sclerosis (Luty et al 2010;Al-Saif et al 2011;Li et al 2015;Gregianin et al 2016). Interestingly, Kv1.2 dysfunction or deletion is also associated with motor neuron disease, where it results in neuronal hyperexcitability (Brew et al 2007;Shibuya et al 2011;Robbins and Tempel 2012;Helbig et al 2016). Therefore, in our final line of experimentation, we examined how modulation of Kv1.2 may be altered in cells expressing the mutant Sig-1R underlying ALS16 (Sig-1R-E102Q; Al-Saif et al 2011).…”

“…As such, Kv1.2 plays an important role in regulating motor neuron hyperexcitability. A recurrent "loss-of-function" mutation in KCNA2 was recently identified which results in hereditary spastic paraplegia (Helbig et al 2016). Hyperexcitability has also been observed in amyotrophic lateral sclerosis (ALS) patients Do-Ha et al 2018;Fogarty 2018), with the degree of hyperexcitability correlating with patient survival (Kanai et al 2012).…”

Rare disease models provide insight into inherited forms of neurodegeneration

“…Historically HSP was grouped into two classifications: 'pure HSP' exclusively exhibiting lower limb spasticity and 'complicated HSP' in which patients presented with additional symptoms including dementia, seizures and amyotrophy 1,2 . Worldwide the prevalence of HSP ranges from <1 -6 per 100,000, though some forms of the condition have been identified in only a few families 3 .…”