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Int J Mol Sci
2021 May 07;229:. doi: 10.3390/ijms22094986.
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Novel KCND3 Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt KV4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties.
Zanni G
,
Hsiao CT
,
Fu SJ
,
Tang CY
,
Capuano A
,
Bosco L
,
Graziola F
,
Bellacchio E
,
Servidei S
,
Primiano G
,
Soong BW
,
Jeng CJ
.
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KCND3 encodes the voltage-gated potassium channel KV4.3 that is highly expressed in the cerebellum, where it regulates dendritic excitability and calcium influx. Loss-of-function KV4.3 mutations have been associated with dominant spinocerebellar ataxia (SCA19/22). By targeted NGS sequencing, we identified two novel KCND3 missense variants of the KV4.3 channel: p.S347W identified in a patient with adult-onset pure cerebellar syndrome and p.W359G detected in a child with congenital nonprogressive ataxia. Neuroimaging showed mild cerebellar atrophy in both patients. We performed a two-electrode voltage-clamp recording of KV4.3 currents in Xenopus oocytes: both the p.G345V (previously reported in a SCA19/22 family) and p.S347W mutants exhibited reduced peak currents by 50%, while no K+ current was detectable for the p.W359G mutant. We assessed the effect of the mutations on channel gating by measuring steady-state voltage-dependent activation and inactivation properties: no significant alterations were detected in p.G345V and p.S347W disease-associated variants, compared to controls. KV4.3 expression studies in HEK293T cells showed 53% (p.G345V), 45% (p.S347W) and 75% (p.W359G) reductions in mutant protein levels compared with the wildtype. The present study broadens the spectrum of the known phenotypes and identifies additional variants for KCND3-related disorders, outlining the importance of SCA gene screening in early-onset and congenital ataxia.
An,
Modulation of A-type potassium channels by a family of calcium sensors.
2000, Pubmed,
Xenbase
An,
Modulation of A-type potassium channels by a family of calcium sensors.
2000,
Pubmed
,
Xenbase
Bertini,
Nonprogressive congenital ataxias.
2018,
Pubmed
Carrasco-Marina,
[De novo sporadic mutation in the KCND3 gene in a patient with early onset chronic ataxia].
2019,
Pubmed
Choi,
Genetic Variants Associated with Episodic Ataxia in Korea.
2017,
Pubmed
Coutelier,
A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies.
2017,
Pubmed
Coutelier,
Efficacy of Exome-Targeted Capture Sequencing to Detect Mutations in Known Cerebellar Ataxia Genes.
2018,
Pubmed
Duarri,
The L450F [Corrected] mutation in KCND3 brings spinocerebellar ataxia and Brugada syndrome closer together.
2013,
Pubmed
Duarri,
Mutations in potassium channel kcnd3 cause spinocerebellar ataxia type 19.
2012,
Pubmed
Hoffman,
K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons.
1997,
Pubmed
Hsiao,
Novel SCA19/22-associated KCND3 mutations disrupt human KV 4.3 protein biosynthesis and channel gating.
2019,
Pubmed
Hsieh,
Infant and adult SCA13 mutations differentially affect Purkinje cell excitability, maturation, and viability in vivo.
2020,
Pubmed
Hsu,
Contrasting expression of Kv4.3, an A-type K+ channel, in migrating Purkinje cells and other post-migratory cerebellar neurons.
2003,
Pubmed
Huin,
Expanding the phenotype of SCA19/22: Parkinsonism, cognitive impairment and epilepsy.
2017,
Pubmed
Jerng,
Modulatory mechanisms and multiple functions of somatodendritic A-type K (+) channel auxiliary subunits.
2014,
Pubmed
Klockgether,
Spinocerebellar ataxia.
2019,
Pubmed
Krivov,
Improved prediction of protein side-chain conformations with SCWRL4.
2009,
Pubmed
Kurihara,
Novel De Novo KCND3 Mutation in a Japanese Patient with Intellectual Disability, Cerebellar Ataxia, Myoclonus, and Dystonia.
2018,
Pubmed
Lee,
Mutations in KCND3 cause spinocerebellar ataxia type 22.
2012,
Pubmed
Li-Smerin,
alpha-helical structural elements within the voltage-sensing domains of a K(+) channel.
2000,
Pubmed
,
Xenbase
Nadal,
Evidence for the presence of a novel Kv4-mediated A-type K(+) channel-modifying factor.
2001,
Pubmed
,
Xenbase
Paucar,
V374A KCND3 Pathogenic Variant Associated With Paroxysmal Ataxia Exacerbations.
2021,
Pubmed
,
Xenbase
Pollini,
KCND3-Related Neurological Disorders: From Old to Emerging Clinical Phenotypes.
2020,
Pubmed
Richards,
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
2015,
Pubmed
Serôdio,
Cloning of a novel component of A-type K+ channels operating at subthreshold potentials with unique expression in heart and brain.
1996,
Pubmed
,
Xenbase
Smets,
First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy.
2015,
Pubmed
Takimoto,
Palmitoylation of KChIP splicing variants is required for efficient cell surface expression of Kv4.3 channels.
2002,
Pubmed
Wang,
Structural basis for modulation of Kv4 K+ channels by auxiliary KChIP subunits.
2007,
Pubmed
,
Xenbase
