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

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

“…Currently, more than 40 loci underlie the AD SCAs, including repeat expansions, rearrangements and point mutations [ 2 , 3 ]. Recently, loss-of function mutations in KCND3 (potassium voltage-gated channel, Shal-related subfamily, member 3) have been identified causing SCA19/22 [ 4 , 5 ], whereas gain-of function mutations in KCND3 were implicated in Brugada syndrome and atrial fibrillation [ 6 – 8 ]. KCND3 encodes the voltage-gated potassium channel Kv4.3, a membrane protein that consists of six trans-membrane segments (S1-S6) and two intracellular tails.…”

Doctoral Dissertation

“…The reported SCA K V 4.3 mutations exhibit impaired folding and exert a dominant negative effect on trafficking and surface expression of wild‐type K V 4.3 resulting in neuro‐degeneration . Notably, Leu450Phe has been associated with both BrS and SCA . This puzzling observation has not been resolved, but electrophysiological studies revealed Leu450Phe results in a gain‐of‐function of K V 4.3.…”

“…184,187 Notably, Leu450Phe has been associated with both BrS and SCA. 188 This puzzling observation has not been resolved, but electrophysiological studies revealed Leu450Phe results in a gain-of-function of K V 4.3. For the loss-of-function mutations associated with SCA, no cardiac phenotype has been reported to date 184,187 and, similarly, no neuronal phenotype have been reported for the BrS or AF associated gainof-function mutations.…”

A comprehensive study of the voltage gated potassium channel Kv4.3: from functional analysis to molecular dynamics modelling

“…In the case of the Kv4.3 channel, mutations have been linked to heart arrythmias (e.g., Brugada syndrome) and a neurological disorder (e.g., spinocerebellar ataxia 19/22) Giudicessi et al, 2012;Lee et al, 2012). Interestingly, one single mutation has never been reported to cause both diseases in the same individual (Duarri et al, 2013).…”

“…Several inherited and de novo mutations have been reported, and lead to the development of late and early onset cerebellar ataxia, respectively. Mutations which lead to late onset cerebellar atrophy are all loss-of-function and differentially affect the activity and the surface expression of the Kv4.3 channel complex (Duarri et al, , 2013. Heart arrythmias are a group of diseases which may lead to sudden cardiac arrest.…”