A KCNB1 gain of function variant causes developmental delay and speech apraxia but not seizures

Abstract

Objective: Numerous pathogenic variants in KCNB1, which encodes the voltage-gated potassium channel, KV2.1, are linked to developmental and epileptic encephalopathies and associated with loss-of-function, -regulation, and -expression of the channel. Here we describe a novel de novo variant (P17T) occurring in the KV2.1 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.Methods: The autosomal dominant variant was identified using whole exome sequencing (WES). The functional effects of the KCNB1 variant on the encoded KV2.1 channel were investigated using whole-cell patch-clamp recordings.Results: We identified a de novo missense variant in the coding region of the KCNB1 gene, c.49C>A which encodes a p.P17T mutation in the N-terminus of the voltage-gated, KV2.1 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.Interpretation: The clinical evaluation of this KCNB1 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 KCNB1 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 KV2.1 potassium channel, whereas this variant causes a gain-of-function.

Mechanisms underlying morphological and functional changes of cilia in fibroblasts derived from patients bearing ARL3T31A and ARL3T31A/C118F mutations

“…The patient displayed a late onset and generally moderate CRD phenotype when he was a heterozygote for ARL3 T31A . Combined with our studies and previous researches, ARL3 T31A may impact GTP binding or exchange and cilium formation, which may be a loss‐of‐function mechanism 40–42 . Notably, the proband showed severe clinical manifestation due to the compound heterozygous variations of ARL3 T31A/C118F .…”

“…Combined with our studies and previous researches, ARL3 T31A may impact GTP binding or exchange and cilium formation, which may be a loss-of-function mechanism. [40][41][42] Notably, the proband showed severe clinical manifestation due to the compound heterozygous variations of ARL3 T31A/C118F . We surmised that these two variations would cooperate to enhance the occurrence and advancement of RCD.…”

Compensation between FOXP transcription factors maintains proper striatal function

“…Interestingly, variants in the latter have been implicated in apraxia of speech, a phenotype seen in human patients with mutations in Foxp1 or Foxp2. 60 , 61 , 89 Future studies can determine how the downregulation of these genes may affect the phenotypes we observe.…”

Mutant analysis of Kcng4b reveals how the different functional states of the voltage-gated potassium channel regulate ear development

“…The KCNB1 human GOF phenotypes have been associated with epileptic encephalopathy, whereas the KCNB1 LOF phenotypes appear to cause developmental delay and speech defects (Bar et al, 2020;Latypova et al, 2017;Marini et al, 2017;Veale et al, 2022).…”

“…The GWAS study suggests that defects of KCNG4 may be associated with migraine, multiple sclerosis and modulation of the uterine nociceptors excitability during labor (Lafrenière and Rouleau, 2012;Lee et al, 2020;Vilariño-Güell et al, 2019), while targeted deletion of Kcng4 in mice results in male sterility (Regnier et al, 2017) and hydrocephalus (https://www.mousephenotype.org/data/genes/MGI:1913983#phenotypesTab). Some KCNB1 heterozygotes have developmental delay and speech defects (Bar et al, 2020;Latypova et al, 2017;Marini et al, 2017), which may be due to KCNB1 gain-of-function (GOF) (Veale et al, 2022). Speech develops with the contribution of many inputs, including the hearing of sound (Anne et al, 2017).…”