KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patients

Figueroa, Karla P.; Minassian, Natali A.; Stevanin, Giovanni; Waters, Michael F.; Garibyan, Vartan; Forlani, Sylvie; Strzelczyk, Adam; Bürk, Katrin; Brice, Alexis; Dürr, Alexandra; Papazian, Diane M.; Pulst, Stefan M.

doi:10.1002/humu.21165

Cited by 82 publications

(109 citation statements)

References 20 publications

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“…2). We confirmed significant loss of Kv3.3 channel activity due to the p.R420H and p.R423H mutations and a shift in activation curve towards the hyperpolarized direction for p.F448L mutant Kv3.3 (data not shown), as previously described [2,6,16]. We observed that only the Kv3.3 channel carrying the p.S591G variant exhibited a significantly reduced channel activity compared with WT Kv3.3 (22.2% loss at +70 mV) (Fig.…”

Section: Resultssupporting

confidence: 91%

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Functional Analysis Helps to Define KCNC3 Mutational Spectrum in Dutch Ataxia Cases

et al. 2015

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Spinocerebellar ataxia type 13 (SCA13) is an autosomal dominantly inherited neurodegenerative disorder of the cerebellum caused by mutations in the voltage gated potassium channel KCNC3. To identify novel pathogenic SCA13 mutations in KCNC3 and to gain insights into the disease prevalence in the Netherlands, we sequenced the entire coding region of KCNC3 in 848 Dutch cerebellar ataxia patients with familial or sporadic origin. We evaluated the pathogenicity of the identified variants by co-segregation analysis and in silico prediction followed by biochemical and electrophysiological studies. We identified 19 variants in KCNC3 including 2 non-coding, 11 missense and 6 synonymous variants. Two missense variants did not co-segregate with the disease and were excluded as potentially disease-causing mutations. We also identified the previously reported p.R420H and p.R423H mutations in our cohort. Of the remaining 7 missense variants, functional analysis revealed that 2 missense variants shifted Kv3.3 channel activation to more negative voltages. These variations were associated with early disease onset and mild intellectual disability. Additionally, one other missense variant shifted channel activation to more positive voltages and was associated with spastic ataxic gait. Whereas, the remaining missense variants did not change any of the channel characteristics. Of these three functional variants, only one variant was in silico predicted to be damaging and segregated with disease. The other two variants were in silico predicted to be benign and co-segregation analysis was not optimal or could only be partially confirmed. Therefore, we conclude that we have identified at least one novel pathogenic mutation in KCNC3 that cause SCA13 and two additionally potential SCA13 mutations. This leads to an estimate of SCA13 prevalence in the Netherlands to be between 0.6% and 1.3%.

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Section: Resultssupporting

confidence: 91%

“…Two of the missense variants, p.R420H and p.R423H, have previously been reported to be pathogenic as these mutations cause aberrant Kv3.3 channel functioning [2,6,16,18]. The p.R420H mutation was found in four affected members from three different families.…”

Section: Resultsmentioning

confidence: 99%

Functional Analysis Helps to Define KCNC3 Mutational Spectrum in Dutch Ataxia Cases

et al. 2015

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“…The R420H mutation is located in the S4 transmembrane segment, an essential element of the voltage sensor domain. It causes a nonfunctional subunit with dominant negative effects specific to Kv3.3 [6,7].…”

Section: Discussionmentioning

confidence: 99%

Mesial temporal lobe epilepsy in a patient with spinocerebellar ataxia type 13 (SCA13)

Bürk¹,

Strzelczyk²,

Reif³

et al. 2013

International Journal of Neuroscience

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We report a female patient of German descent with a molecular diagnosis of SCA13 who presented with a history of cerebellar ataxia and epilepsy. The underlying mutation R420H had been shown to cause a dominant negative effect on the functional properties of the voltage-gated potassium channel KCNC3. Despite widespread KCNC3 expression in the central nervous system, the patient presented with a left mesiotemporal electroencephalogram focus and left hippocampal sclerosis. This is the first case, which reports an association between mesial temporal lobe epilepsy and spinocerebellar ataxia type 13. This demonstrates that epilepsy of structural-metabolic cause may be contingent upon genetically defined channelopathies.

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“…SCA13 was initially reported in French and Filipino families and is caused by missense mutations in KCNC3, which encodes a voltage-gated potassium channel [Figueroa et al, 2010]. There is a wide phenotypic spectrum that correlates with different missense mutations.…”

Section: Due To Conventional Mutationsmentioning

confidence: 99%

The inherited ataxias: Genetic heterogeneity, mutation databases, and future directions in research and clinical diagnostics

2012

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ABSTRACT:The inherited cerebellar ataxias are a diverse group of clinically and genetically heterogeneous neurodegenerative disorders. Inheritance patterns of these disorders can be complex with autosomal dominant, autosomal recessive, X-linked, and mitochondrial inheritance demonstrated by one or more ataxic syndromes. The broad range of mutation types found in inherited ataxia contributes to the complex genetic etiology of these disorders. The majority of inherited ataxias are caused by repeat expansions; however, conventional mutations are important causes of the rarer dominant and recessive ataxias. Advances in sequencing technology have allowed for much broader testing of these rare ataxia genes. This is relevant to the aims of the Human Variome Project, which aims to collate and store gene variation data through mutation databases. Variant data is currently located in a range of public and commercial resources. Few locus-specific databases have been created to catalogue variation in the dominant ataxia genes although there are several databases for some recessive genes. Developing these resources will facilitate a better understanding of the complex genotypephenotype relationships in these disorders and assist interpretation of gene variants as testing for rarer ataxia genes becomes commonplace.

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KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patients

Cited by 82 publications

References 20 publications

Functional Analysis Helps to Define KCNC3 Mutational Spectrum in Dutch Ataxia Cases

Functional Analysis Helps to Define KCNC3 Mutational Spectrum in Dutch Ataxia Cases

Mesial temporal lobe epilepsy in a patient with spinocerebellar ataxia type 13 (SCA13)

The inherited ataxias: Genetic heterogeneity, mutation databases, and future directions in research and clinical diagnostics

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