XB-ART-56998Ann Clin Transl Neurol January 1, 2019; 6 (7): 1319-1326.
KCNC1-related disorders: new de novo variants expand the phenotypic spectrum.
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.
PubMed ID: 31353862
PMC ID: PMC6649617
Article link: Ann Clin Transl Neurol
Species referenced: Xenopus
Genes referenced: kcnc1 kcnc2 kcnc4
GO keywords: potassium channel activity
Disease Ontology terms: progressive myoclonus epilepsy 7
OMIMs: MYOCLONIC EPILEPSY OF UNVERRICHT AND LUNDBORG
Article Images: [+] show captions
|Figure 1. (A) Pedigrees of the five unrelated affected individuals (closed symbols) with de novo KCNC1 variants and status of healthy family members (open symbols). wt indicates for wild type. (B) Graphical illustration of the KV3.1 channel demonstrates the domain structures. The positions of the identified variants (Cys208Tyr, Thr399Met, Ala421Val) and the previously published variants (Arg320His and Arg339*) are highlighted with stars. The plus sign illustrates the positively charged arginine in the voltage‐sensing S4 segment.21 (C) Amino acid sequences across different species indicate that the variants are localized in highly conserved regions. (D) Images of patient 2 at 11 years of age show hypertelorism, long palpebral fissures, broad nose, large ears, diastema, small chin, and sandal gap. The hands of patient 2 do not have any dysmorphic features.|
References [+] :
Aggarwal, Contribution of the S4 segment to gating charge in the Shaker K+ channel. 1996, Pubmed, Xenbase