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Ann Clin Transl Neurol
2019 Jul 01;67:1263-1272. doi: 10.1002/acn3.50822.
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Encephalopathies with KCNC1 variants: genotype-phenotype-functional correlations.
Cameron JM
,
Maljevic S
,
Nair U
,
Aung YH
,
Cogné B
,
Bézieau S
,
Blair E
,
Isidor B
,
Zweier C
,
Reis A
,
Koenig MK
,
Maarup T
,
Sarco D
,
Afenjar A
,
Huq AHMM
,
Kukolich M
,
Billette de Villemeur T
,
Nava C
,
Héron B
,
Petrou S
,
Berkovic SF
.
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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 Kv 3.1 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.
Figure 1. Facial features of patient 3 showing a large mouth, smooth philtrum, upâslanting palpebral fissure, and dental enlargement.
Figure 2. Functional expression of Kv3.1 variants in Xenopus laevis oocytes (A) Schematic of the Kv3.1 channel with putative positions of variants reported in this study (Orange â Developmental and Epileptic Encephalopathy [DEE] variant; Green â Developmental Encephalopathy variants [DE]; Light blue â variant of uncertain significance). The dashed line shows the distal part of the Câterminus that is present only in the longer transcript variant (Kv3.1b) indicating that the A513V variant is only found in this transcript. (B) Representative traces of wholeâcell currents recorded from Xenopus laevis oocytes injected with the same amount of cRNA encoding Kv3.1 wildâtype (Kv3.1a and Kv3.1b) and different variants during 0.5 sec voltage steps ranging from â 60 mV to + 60 mV. Insets show blown up tail currents, which were analyzed to generate conductanceâvoltage relationships for WT and mutant channels shown in E. (C, D) Current amplitudes analyzed at the end of the voltage step to + 60 mV and normalized to the mean current amplitude of the corresponding WT recorded on the same day; Kv3.1a (n = 136), A421V (n = 62), R317H (n = 32), Q492X (n = 30), R339X (n = 48), and water (n = 35); Kv3.1b (n = 15), A513V (n = 17). ****P < 0.0001, using oneâway ANOVA with Dunnettâs multiple comparisons test (C). MannâWhitney nonâparametric test (D) revealed P = 0.5. (E) Conductanceâvoltage relationships for the WT transcripts and variants showing current amplitudes above the background level. V0.5 and k values were as follows: for Kv3.1a 23 ± 2 mV, 12.8 ± 0.6 (n = 37), for Kv3.1b 33.8 ± 1.1 mV, 12.80 ± 1.04 (n = 18), for Q492X 15 ± 3 mV, 12.7 ± 0.8 (n = 19), and for A513V 29 ± 2 mV, 11.6 ± 0.6 (n = 21); V0.5 Kv3.1a vs V0.5 Kv3.1b, ANOVA with Tukeyâs multiple comparisons test.
Figure 3. Dominantânegative effect of Kv3.1 variants. (A) Representative current traces recorded from Xenopus laevis oocytes injected with the same amount of cRNA encoding Kv3.1a wildâtype with addition of either H2O or the same amount cRNA encoding Kv3.1 variants in a 1:1 ratio. (B) Current amplitudes analyzed at the end of the voltage step to + 60 mV and normalized to the mean current amplitude of WT + H2O recorded on the same day revealed a significant reduction for R317H and R339X but not for the A421V coexpression, ***P < 0.001, **P < 0.01 using oneâway ANOVA with Dunnettâs multiple comparisons test; WT + H2O (n = 111), WT + A421V (n = 62); WT + R317H (n = 11); WT + Q492X (n = 21); WT + R339X (n = 17). (C) Conductanceâvoltage relationships of the WT and its coexpressions with A421V, R317H and R339X. V0.5 and slope factor (k) values were as follows: for WT + H2O 18.2 ± 1.4 mV, 12.4 ± 0.4 (n = 27), for WT + A421V 16.6 ± 1.8, 15.2 ± 0.4 (n = 36), for WT + R317H 21.1 ± 4.5 mV, 17.8 ± 1.9 (n = 8), for WT + Q492X 25 ± 3 mV, 13.9 ± 0.5 (n = 12), and for WT + R339X 15.8 ± 3.1 mV, 12.2 ± 1.1 (n = 15).
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