TY - JOUR
T1 - Mono-allelic KCNB2 variants lead to a neurodevelopmental syndrome caused by altered channel inactivation
AU - Bhat, Shreyas
AU - Rousseau, Justine
AU - Michaud, Coralie
AU - Lourenço, Charles Marques
AU - Stoler, Joan M.
AU - Louie, Raymond J.
AU - Clarkson, Lola K.
AU - Lichty, Angie
AU - Koboldt, Daniel C.
AU - Reshmi, Shalini C.
AU - Sisodiya, Sanjay M.
AU - Hoytema van Konijnenburg, Eva M.M.
AU - Koop, Klaas
AU - van Hasselt, Peter M.
AU - Démurger, Florence
AU - Dubourg, Christèle
AU - Sullivan, Bonnie R.
AU - Hughes, Susan S.
AU - Thiffault, Isabelle
AU - Tremblay, Elisabeth Simard
AU - Accogli, Andrea
AU - Srour, Myriam
AU - Blunck, Rikard
AU - Campeau, Philippe M.
N1 - Publisher Copyright:
© 2024 American Society of Human Genetics
PY - 2024/4/4
Y1 - 2024/4/4
N2 - Ion channels mediate voltage fluxes or action potentials that are central to the functioning of excitable cells such as neurons. The KCNB family of voltage-gated potassium channels (Kv) consists of two members (KCNB1 and KCNB2) encoded by KCNB1 and KCNB2, respectively. These channels are major contributors to delayed rectifier potassium currents arising from the neuronal soma which modulate overall excitability of neurons. In this study, we identified several mono-allelic pathogenic missense variants in KCNB2, in individuals with a neurodevelopmental syndrome with epilepsy and autism in some individuals. Recurrent dysmorphisms included a broad forehead, synophrys, and digital anomalies. Additionally, we selected three variants where genetic transmission has not been assessed, from two epilepsy studies, for inclusion in our experiments. We characterized channel properties of these variants by expressing them in oocytes of Xenopus laevis and conducting cut-open oocyte voltage clamp electrophysiology. Our datasets indicate no significant change in absolute conductance and conductance-voltage relationships of most disease variants as compared to wild type (WT), when expressed either alone or co-expressed with WT-KCNB2. However, variants c.1141A>G (p.Thr381Ala) and c.641C>T (p.Thr214Met) show complete abrogation of currents when expressed alone with the former exhibiting a left shift in activation midpoint when expressed alone or with WT-KCNB2. The variants we studied, nevertheless, show collective features of increased inactivation shifted to hyperpolarized potentials. We suggest that the effects of the variants on channel inactivation result in hyper-excitability of neurons, which contributes to disease manifestations.
AB - Ion channels mediate voltage fluxes or action potentials that are central to the functioning of excitable cells such as neurons. The KCNB family of voltage-gated potassium channels (Kv) consists of two members (KCNB1 and KCNB2) encoded by KCNB1 and KCNB2, respectively. These channels are major contributors to delayed rectifier potassium currents arising from the neuronal soma which modulate overall excitability of neurons. In this study, we identified several mono-allelic pathogenic missense variants in KCNB2, in individuals with a neurodevelopmental syndrome with epilepsy and autism in some individuals. Recurrent dysmorphisms included a broad forehead, synophrys, and digital anomalies. Additionally, we selected three variants where genetic transmission has not been assessed, from two epilepsy studies, for inclusion in our experiments. We characterized channel properties of these variants by expressing them in oocytes of Xenopus laevis and conducting cut-open oocyte voltage clamp electrophysiology. Our datasets indicate no significant change in absolute conductance and conductance-voltage relationships of most disease variants as compared to wild type (WT), when expressed either alone or co-expressed with WT-KCNB2. However, variants c.1141A>G (p.Thr381Ala) and c.641C>T (p.Thr214Met) show complete abrogation of currents when expressed alone with the former exhibiting a left shift in activation midpoint when expressed alone or with WT-KCNB2. The variants we studied, nevertheless, show collective features of increased inactivation shifted to hyperpolarized potentials. We suggest that the effects of the variants on channel inactivation result in hyper-excitability of neurons, which contributes to disease manifestations.
KW - channel inactivation, neurodevelopmental disorders, voltage-gated potassium channels
KW - dysmorphism
KW - epilepsy
KW - global developmental delay
KW - KCNB2
UR - http://www.scopus.com/inward/record.url?scp=85188992203&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2024.02.014
DO - 10.1016/j.ajhg.2024.02.014
M3 - Article
C2 - 38503299
AN - SCOPUS:85188992203
SN - 0002-9297
VL - 111
SP - 761
EP - 777
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -