The L450P mutation in KCND3 brings spinocerebellar ataxia and Brugada syndrome closer together

Abstract

The autosomal dominant cerebellar ataxias (SCAs) are progressive neurodegenerative disorders caused by atrophy of the cerebellum leading to progressive ataxia of gait and limbs, and speech and eye movement difficulties [1]. The SCAs are genetically heterogeneous and 22 causal genes have already been identified [12]. With the introduction of next-generation sequencing, novel SCA genes are being rapidly discovered and many more will certainly follow.

Recently, we and others have identified loss-of-function mutations in KCND3 as causing SCA19 and SCA22 (SCA19/22) [34], but gain-of-function mutations in KCND3 were also implicated in Brugada syndrome and atrial fibrillation [56]. KCND3 encodes for the voltage-gated potassium channel Kv4.3, which mediates A-type potassium currents in neurons (I A) and in the heart (I to), although the disease mechanisms underlying these allelic disorders are not yet understood.
To determine the disease frequency of SCA19/22 in Europe, we screened 366 familial ataxia cases. Most were of French origin and had tested negative for SCA1–3, SCA6, SCA7, SCA17, SCA23, and DRLPA mutations. The complete coding sequence and exon–intron boundaries of KCND3 were screened using high-resolution melting (HRM) analysis (LightScanner, Bioke; for primer sequences, see Table S1).
We discovered a French man (AAD-722-001) carrying the c.1348C>T, p.L450P mutation, which was reported to be associated with Brugada syndrome and was proven to result in a gain of Kv4.3 channel function [4]. This patient displayed a cerebellar gait ataxia at age 39, associated with pyramidal signs. However, at age 46 years, he has not yet presented with any heart problems. Since this man might be at risk for pathological heart palpitations and lethal ventricular arrhythmias, he should be screened for ECG abnormalities. This result emphasizes that the p.L450P mutation may predispose to both ataxia and ventricular arrhythmias, as might be the case for additional mutations associated with heritable heart syndromes such as Brugada syndrome and spinocerebellar ataxia that are located within the sixth transmembrane domain and the C-terminal tail of Kv4.3.
Additionally, we identified a heterozygous variant, c. 1840C>T, p.P614S, in a French woman (AAD-114-009), who had developed a cerebellar gait ataxia with decreased reflexes and vibration sense in the ankles at the age of 59 years. This variant was not reported in any genetic database or in 400 French controls, but was found in one Dutch control (1/400). No additional family members were available for co-segregation testing. The p.P614S variant did not alter Kv4.3’s cellular localization (Fig. 1a) and did not show any defects in channel activity (Fig. 1b) or channel-gating properties (Fig. 1c, d), suggesting that the p.P614S variant must be a very rare polymorphism.
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