TY - JOUR
T1 - High-throughput evaluation of epilepsy-associated KCNQ2 variants reveals functional and pharmacological heterogeneity
AU - Vanoye, Carlos G.
AU - Desai, Reshma R.
AU - Ji, Zhigang
AU - Adusumilli, Sneha
AU - Jairam, Nirvani
AU - Ghabra, Nora
AU - Joshi, Nishtha
AU - Fitch, Eryn
AU - Helbig, Katherine L.
AU - McKnight, Dianalee
AU - Lindy, Amanda S.
AU - Zou, Fanggeng
AU - Helbig, Ingo
AU - Cooper, Edward C.
AU - George, Alfred L.
N1 - Funding Information:
The authors thank Jean-Marc DeKeyser for help with molecular biology and for creating the image in Supplemental Figure 1. This work was supported by NIH grant NS108874.
Funding Information:
of a Scientific Advisory Board for Amgen, received payments from Merck and Amgen for consulting, and received grant support from Praxis Precision Medicines and Tevard Biosciences. ECC has served as a consultant to and received investigator-initiated research grants from SciFluor Life Sciences, Knopp Biosciences, and Xenon Pharmaceuticals. This consultancy work and sponsored research was approved according to the conflict of interest policies of Baylor College of Medicine.
Publisher Copyright:
© 2022, Vanoye et al.
PY - 2022/3/8
Y1 - 2022/3/8
N2 - Hundreds of genetic variants in KCNQ2 encoding the voltage-gated potassium channel KV7.2 are associated with early onset epilepsy and/or developmental disability, but the functional consequences of most variants are unknown. Absent functional annotation for KCNQ2 variants hinders identification of individuals who may benefit from emerging precision therapies. We employed automated patch clamp recordings to assess at, to our knowledge, an unprecedented scale the functional and pharmacological properties of 79 missense and 2 inframe deletion KCNQ2 variants. Among the variants we studied were 18 known pathogenic variants, 24 mostly rare population variants, and 39 disease-associated variants with unclear functional effects. We analyzed electrophysiological data recorded from 9,480 cells. The functional properties of 18 known pathogenic variants largely matched previously published results and validated automated patch clamp for this purpose. Unlike rare population variants, most disease-associated KCNQ2 variants exhibited prominent loss-of-function with dominant-negative effects, providing strong evidence in support of pathogenicity. All variants responded to retigabine, although there were substantial differences in maximal responses. Our study demonstrated that dominant-negative loss-of-function is a common mechanism associated with missense KCNQ2 variants. Importantly, we observed genotype-dependent differences in the response of KCNQ2 variants to retigabine, a proposed precision therapy for KCNQ2 developmental and epileptic encephalopathy.
AB - Hundreds of genetic variants in KCNQ2 encoding the voltage-gated potassium channel KV7.2 are associated with early onset epilepsy and/or developmental disability, but the functional consequences of most variants are unknown. Absent functional annotation for KCNQ2 variants hinders identification of individuals who may benefit from emerging precision therapies. We employed automated patch clamp recordings to assess at, to our knowledge, an unprecedented scale the functional and pharmacological properties of 79 missense and 2 inframe deletion KCNQ2 variants. Among the variants we studied were 18 known pathogenic variants, 24 mostly rare population variants, and 39 disease-associated variants with unclear functional effects. We analyzed electrophysiological data recorded from 9,480 cells. The functional properties of 18 known pathogenic variants largely matched previously published results and validated automated patch clamp for this purpose. Unlike rare population variants, most disease-associated KCNQ2 variants exhibited prominent loss-of-function with dominant-negative effects, providing strong evidence in support of pathogenicity. All variants responded to retigabine, although there were substantial differences in maximal responses. Our study demonstrated that dominant-negative loss-of-function is a common mechanism associated with missense KCNQ2 variants. Importantly, we observed genotype-dependent differences in the response of KCNQ2 variants to retigabine, a proposed precision therapy for KCNQ2 developmental and epileptic encephalopathy.
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U2 - 10.1172/jci.insight.156314
DO - 10.1172/jci.insight.156314
M3 - Article
C2 - 35104249
AN - SCOPUS:85125906744
SN - 2379-3708
VL - 7
JO - JCI insight
JF - JCI insight
IS - 5
M1 - e156314
ER -