Loss of Function of KCNC1 is associated with intellectual disability without seizures

Poirier, Karine; Viot, Géraldine; Lombardi, Laura; Jauny, Clémence; Billuart, Pierre; Bienvenu, Thierry

doi:10.1038/ejhg.2017.3

Cited by 27 publications

(30 citation statements)

References 28 publications

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“…E) . In contrast to the haploinsufficiency of the truncating variant in the previously described family with ID, the variant Thr399Met, also causing ID alone, showed a pronounced dominant‐negative effect . Our current data do thus not reveal a clear correlation between the electrophysiological properties of mutant channels and clinical phenotypes.…”

Section: Discussioncontrasting

confidence: 85%

“…The phenotype of patient 2 (Thr399Met), who showed ID and dysmorphic features, is more similar to the family reported by Poirier et al . in which three affected members carried the nonsense mutation Arg339* . All three had similar dysmorphic features, which however differed from those observed in patient 2 (Fig.…”

Section: Discussionmentioning

confidence: 61%

“…The respective phenotype is similar to Unverricht‐Lundborg disease . Subsequently, one nonsense variant (c.1015C > T, p.Arg339*) has been identified in three affected members of single family with ID without seizures . Here, we report three new pathogenic de novo missense variants in KCNC1 in five unrelated patients.…”

Section: Introductionmentioning

confidence: 73%

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KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum

Park

Koko

Hedrich

et al. 2019

Ann Clin Transl Neurol

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A recurrent de novo missense variant in KCNC1, encoding a voltage‐gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic‐clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant‐negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism.

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Section: Discussioncontrasting

confidence: 85%

Section: Discussionmentioning

confidence: 61%

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KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum

Park

Koko

Hedrich

et al. 2019

Ann Clin Transl Neurol

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“…When analyzed in vitro , the PME causing mutation was shown to have a dominant‐negative loss of function effect . Subsequently, a truncating variant in KCNC1 , p.Arg339X, was described in three related individuals with intellectual disability (ID) and dysmorphic features without epilepsy . This raises the possibility of a wider spectrum of phenotypes associated with pathogenic KCNC1 variants.…”

Section: Introductionmentioning

confidence: 99%

Encephalopathies with KCNC1 variants: genotype‐phenotype‐functional correlations

Cameron

Maljevic

Nair

et al. 2019

Ann Clin Transl Neurol

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Objective To analyze clinical phenotypes associated with KCNC1 variants other than the Progressive Myoclonus Epilepsy‐causing variant p.Arg320His, determine the electrophysiological functional impact of identified variants and explore genotype‐phenotype‐physiological correlations. Methods Ten cases with putative pathogenic variants in KCNC1 were studied. Variants had been identified via whole‐exome sequencing or gene panel testing. Clinical phenotypic data were analyzed. To determine functional impact of variants detected in the Kv3.1 channel encoded by KCNC1, Xenopus laevis oocyte expression system and automated two‐electrode voltage clamping were used. Results Six unrelated patients had a Developmental and Epileptic Encephalopathy and a recurrent de novo variant p.Ala421Val (c.1262C > T). Functional analysis of p.Ala421Val revealed loss of function through a significant reduction in whole‐cell current, but no dominant‐negative effect. Three patients had a contrasting phenotype of Developmental Encephalopathy without seizures and different KCNC1 variants, all of which caused loss of function with reduced whole‐cell currents. Evaluation of the variant p.Ala513Val (c.1538C > T) in the tenth case, suggested it was a variant of uncertain significance. Interpretation These are the first reported cases of Developmental and Epileptic Encephalopathy due to KCNC1 mutation. The spectrum of phenotypes associated with KCNC1 is now broadened to include not only a Progressive Myoclonus Epilepsy, but an infantile onset Developmental and Epileptic Encephalopathy, as well as Developmental Encephalopathy without seizures. Loss of function is a key feature, but definitive electrophysiological separation of these phenotypes has not yet emerged.

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“…Also, Kv 3.1 is involved in regulating the duration and amplitude of the presynaptic potential, thus controlling evoked neurotransmitter release [40]. Given their essential role in modulating neuronal activity, reduction of Kv 3.1 channel expression and/or activity has been linked to neurodegenerative disorders such as Alzheimer’s disease [41], inherited ataxia [42, 43], schizophrenia [44] and intellectual disability [45]. Recently, a role of Kv 3.1 in causing a distinct form of progressive myoclonus epilepsy called myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK) has been described [46].…”

Section: Discussionmentioning

confidence: 99%

A Potassium-Selective Current Affected by Micromolar Concentrations of Anion Transport Inhibitors

Costa

Civello

Bernardinelli

et al. 2018

Cell Physiol Biochem

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Background/Aims: In the human genome, more than 400 genes encode ion channels, which are ubiquitously expressed and often coexist and participate in almost all physiological processes. Therefore, ion channel blockers represent fundamental tools in discriminating the contribution of individual channel types to a physiological phenomenon. However, unspecific effects of these compounds may represent a confounding factor. Three commonly used chloride channel inhibitors, i.e. 4,4′-diisothiocyano-2,2′-stilbene-disulfonic acid (DIDS), 5-nitro-2-[(3-phenylpropyl) amino]benzoic acid (NPPB) and the anti-inflammatory drug niflumic acid were tested to identify the lowest concentration effective on Cl^- channels and ineffective on K⁺ channels. Methods: The activity of the above mentioned compounds was tested by whole cell patch-clamp on the swelling-activated Cl^- current ICl,swell and on the endogenous voltage-dependent, outwardly rectifying K⁺ selective current in human kidney cell lines (HEK 293/HEK 293 Phoenix). Results: Micromolar (1-10 µM) concentrations of DIDS and NPPB could not discriminate between the Cl^- and K⁺ selective currents. Specifically, 1 µM DIDS only affected the K⁺ current and 10 µM NPPB equally affected the Cl^- and K⁺ currents. Only relatively high (0.1-1 mM) concentrations of DIDS and prolonged (5 minutes) exposure to 0.1-1 mM NPPB preferentially suppressed the Cl^- current. Niflumic acid preferentially inhibited the Cl^- current, but also significantly affected the K⁺ current. The endogenous voltage-dependent, outwardly rectifying K⁺ selective current in HEK 293/HEK 293 Phoenix cells was shown to arise from the Kv 3.1 channel, which is extensively expressed in brain and is involved in neurological diseases. Conclusion: The results of the present study underscore that sensitivity of a given physiological phenomenon to the Cl^- channel inhibitors NPPB, DIDS and niflumic acid may actually arise from an inhibition of Cl^- channels but can also result from an inhibition of voltage-dependent K⁺ channels, including the Kv 3.1 channel. The use of niflumic acid as anti-inflammatory drug in patients with concomitant Kv 3.1 dysfunction may result contraindicated.

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Loss of Function of KCNC1 is associated with intellectual disability without seizures

Cited by 27 publications

References 28 publications

KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum

KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum

Encephalopathies with KCNC1 variants: genotype‐phenotype‐functional correlations

A Potassium-Selective Current Affected by Micromolar Concentrations of Anion Transport Inhibitors

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