Veale, Emma, L., Golluscio, Alessia, Grand, Katheryn, Graham, John, M. and Mathie, Alistair (2022) A KCNB1 gain of function variant causes developmental delay and speech apraxia but not seizures. Frontiers in pharmacology, 13 (109331). pp. 1-12. ISSN 1663-9812

Preview

Text Veale et al 2022.pdf - Published Version Available under License Creative Commons Attribution. Download (2MB) | Preview

Abstract

Numerous pathogenic variants in , which encodes the voltage-gated potassium channel, K2.1, are linked to developmental and epileptic encephalopathies and associated with loss-of-function, -regulation, and -expression of the channel. Here we describe a novel variant (P17T) occurring in the K2.1 channel that is associated with a gain-of-function (GoF), with altered steady-state inactivation and reduced sensitivity to the selective toxin, guanxitoxin-1E and is clinically associated with neurodevelopmental disorders, without seizures. The autosomal dominant variant was identified using whole exome sequencing (WES). The functional effects of the variant on the encoded K2.1 channel were investigated using whole-cell patch-clamp recordings. We identified a missense variant in the coding region of the gene, c.49C>A which encodes a p.P17T mutation in the N-terminus of the voltage-gated, K2.1 potassium channel. Electrophysiological studies measuring the impact of the variant on the functional properties of the channel, identified a gain of current, rightward shifts in the steady-state inactivation curve and reduced sensitivity to the blocker, guanxitoxin-1E. The clinical evaluation of this mutation describes a novel variant that is associated with global developmental delays, mild hypotonia and joint laxity, but without seizures. Most of the phenotypic features described are reported for other variants of the gene. However, the absence of early-onset epileptic disorders is a much less common occurrence. This lack of seizure activity may be because other variants reported have resulted in loss-of-function of the encoded K2.1 potassium channel, whereas this variant causes a gain-of-function.

Actions (login required)

View Item