First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy

Abstract

BackgroundIdentification of the first de novo mutation in potassium voltage-gated channel, shal-related subfamily, member 3 (KCND3) in a patient with complex early onset cerebellar ataxia in order to expand the genetic and phenotypic spectrum.MethodsWhole exome sequencing in a cerebellar ataxia patient and subsequent immunocytochemistry, immunoblotting and patch clamp assays of the channel were performed.ResultsA de novo KCND3 mutation (c.877_885dupCGCGTCTTC; p.Arg293_Phe295dup) was found duplicating the RVF motif and thereby adding an extra positive charge to voltage-gated potassium 4.3 (Kv4.3) in the voltage-sensor domain causing a severe shift of the voltage-dependence gating to more depolarized voltages. The patient displayed a severe phenotype with early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity.ConclusionsWe identified a de novo KCND3 mutation causing the most marked change in Kv4.3’s channel properties reported so far, which correlated with a severe and unique spinocerebellar ataxia (SCA) type 19/22 disease phenotype.

Novel SCA19/22‐associated KCND3 mutations disrupt human K V 4.3 protein biosynthesis and channel gating

“…In fact, the phenotypic spectrum of SCA19/ 22 has been widened to include a wide variety of different movement disorders, such as myoclonus, dystonia, and Parkinsonism (Duarri et al, 2012;Huin et al, 2017;Kurihara et al, 2018). Interestingly, myoclonus and dystonia were also observed in our patients carrying the novel p.C317Y and p.P375S mutations (Table 1) | 2101 Kurihara et al, 2018;Paucar et al, 2018;Smets et al, 2015). Earlier, a Japanese SCA19/22 patient with the p.T377M mutation was not reported to exhibit significant cognitive impairment (Lee et al, 2012).…”

“…Another intriguing issue on phenotypic heterogeneity in SCA19/22 concerns the extent of intellectual disability (Huin et al, ; Kurihara et al, ; Paucar et al, ; Smets et al, ). Earlier, a Japanese SCA19/22 patient with the p.T377M mutation was not reported to exhibit significant cognitive impairment (Lee et al, ).…”

“…Among them, SCA19/22 (MIM# 607346) is associated with mutations in the KCND3 gene that encodes the K V 4.3 subunit (Duarri et al, 2012;Lee et al, 2012). To date, 15 SCA19/22-associated KCND3 mutations have been identified in patients with cerebellar ataxia (Choi et al, 2017;Coutelier et al, 2017Coutelier et al, , 2018Duarri et al, 2012Duarri et al, , 2013Huin et al, 2017;Kurihara et al, 2018;Lee et al, 2012;Paucar et al, 2018;Smets et al, 2015).…”

Hypothalamic transcriptomic alterations in male and female California mice (Peromyscus californicus) developmentally exposed to bisphenol A or ethinyl estradiol

“…In humans, mutation of KCND3 is associated with cerebellar ataxia, intellectual disability, epilepsy, attention deficit disorders, and other clinical signs (Smets et al. ). Similar to the current findings, estrogen decreases transcriptional expression of Kv4.3 in the myometrium (Song et al.…”

Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking

“…Originally implicated for their role in epilepsy (Maljevic & Lerche, 2014; Smets et al, 2015), studies show that calcium-activated (K Ca ), voltage-dependent (K V ), and G protein-coupled inwardly-rectifying (K ir ) K + channels are targets for both acute and chronic effects of ethanol (Hopf et al, 2011; Mayfield, Blednov, & Harris, 2015; Mulholland, 2012; Mulholland, Hopf, et al, 2009). Additionally, preclinical studies have demonstrated that chronic ethanol reduces the function and trafficking of K Ca 2 ( Kcnn ), K V 4.2 ( Kcnd2 ), and K V 7.2 ( Kcnq2 ) channels in the nucleus accumbens (NAc) and hippocampus (Hopf et al, 2010; McGuier et al, 2015; Mulholland, Spencer, Hu, Kroener, & Chandler, 2015; Padula et al, 2015; Spencer, Mulholland, & Chandler, In Press), and pharmacologically enhancing K Ca 2 and K V 7 channel function attenuated voluntary drinking in rodents (Hopf et al, 2011; Knapp, O’Malley, Datta, & Ciraulo, 2014; McGuier et al, 2015; Padula et al, 2013).…”