A novel KCNQ3 mutation in familial epilepsy with focal seizures and intellectual disability

Abstract

SUMMARYMutations in the KCNQ2 gene encoding for voltage-gated potassium channel subunits have been found in patients affected with early onset epilepsies with wide phenotypic heterogeneity, ranging from benign familial neonatal seizures (BFNS) to epileptic encephalopathy with cognitive impairment, drug resistance, and characteristic electroencephalography (EEG) and neuroradiologic features. By contrast, only few KCNQ3 mutations have been rarely described, mostly in patients with typical BFNS. We report clinical, genetic, and functional data from a family in which early onset epilepsy and neurocognitive deficits segregated with a novel mutation in KCNQ3 (c.989G>T; p.R330L). Electrophysiological studies in mammalian cells revealed that incorporation of KCNQ3 R330L mutant subunits impaired channel function, suggesting a pathogenetic role for such mutation. The degree of functional impairment of channels incorporating KCNQ3 R330L subunits was larger than that of channels carrying another KCNQ3 mutation affecting the same codon but leading to a different amino acid substitution (p.R330C), previously identified in two families with typical BFNS. These data suggest that mutations in KCNQ3, similarly to KCNQ2, can be found in patients with more severe phenotypes including intellectual disability, and that the degree of the functional impairment caused by mutations at position 330 in KCNQ3 may contribute to clinical disease severity.

Novel genetic causes for cerebral visual impairment

“…[57][58][59][60][61][62][63][64][65] However, recently two additional families with seizures and variants in KCNQ3 have been reported in which family members had various IQ levels from severe ID to normal. 66,67 Therefore, the phenotypic spectrum of KCNQ3 variants appeared to be broader than benign epilepsy only and might well include CVI.…”

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

“…Mutations in other KCNQ homologs, KCNQ2 and less commonly KCNQ3, can also result in epilepsy either by loss-of-function or by gainof-function effects. 7,[22][23][24] In neurons, Kv7.5 is important for regulation of the M-type current, and hence firing rates. The M-current is a slowly activating and deactivating neuronal potassium current that plays a crucial role in regulating neuronal excitability by impeding repetitive (E) Relative functional channel expression.…”

Novel KCNQ3 Mutation in a Large Family with Benign Familial Neonatal Epilepsy: A Rare Cause of Neonatal Seizures

“…Only a few reports involved functional characterization of KCNQ3 mutations [Uhehara et al, 2008;Suguira et al, 2009;Soldovieri et al, 2014;Miceli et al, 2015a, b]. The results varied from mere reduction in current amplitudes [Suguira et al, 2009;Soldovieri et al, 2014] over a dominant negative effect associated with BFNS [Uhehara et al, 2008] or with a more severe phenotype with intellectual disability [Miceli et al, 2015b], to the mentioned gain of function in severe epilepsy [Miceli et al, 2015 a ].…”