Nongenetic factors influence severity of episodic ataxia type 1 in monozygotic twins

Abstract

Objective: Episodic ataxia type 1 (EA1) is a monogenic channelopathy caused by mutations of the potassium channel gene KCNA1. Affected individuals carrying the same mutation can exhibit considerable variability in the severity of ataxia, neuromyotonia, and other associated features. We investigated the phenotypic heterogeneity of EA1 in 2 sets of identical twins to determine the contribution of environmental factors to disease severity. One of the mutations was also found in a distantly related family, providing evidence of the influence of genetic background on the EA1 phenotype. Methods:We evaluated 3 families with an EA1 phenotype, 2 of which included monozygotic twins. We sequenced the KCNA1 gene and studied the biophysical consequences of the mutations in HEK cells. Results:We identified a new KCNA1 mutation in each pair of twins. Both pairs reported striking differences in the clinical severity of symptoms. The F414S mutation identified in one set of twins also occurred in a distantly related family in which seizures complicated the EA1 phenotype. The other twins had an R307C mutation, the first EA1 mutation to affect an arginine residue in the voltage-sensor domain. Both mutants when expressed exerted a dominant-negative effect on wild-type channels. Conclusion:These results broaden the range of KCNA1 mutations and reveal an unexpectedly large contribution of nongenetic factors to phenotypic variability in EA1. The occurrence of epilepsy in 1 of 2 families with the F414S mutation suggests an interplay of KCNA1 with other genetic factors. Neurology Episodic ataxia type 1 (EA1) is characterized by brief paroxysms of ataxia and interictal myokymia.1 It is caused by heterozygous point mutations in the voltage-gated K V 1.1 potassium channel ␣-subunit, encoded by KCNA1.2 Scrutiny of genetically confirmed kindreds reveals considerable phenotypic heterogeneity with respect to severity of ataxia and presence of additional features such as epilepsy.1 Hitherto, attempts to account for phenotypic variability have concentrated on differences among distinct KCNA1 mutations with respect to their functional consequences when expressed in vitro. All EA1 mutations cause a loss of function, typically measured as a decrease in current density.1 Mutations associated with a severe phenotype have a dominant negative effect on wild-type channel function.3-5 A recent study in neurons has shown that KCNA1 mutations differentially affect action potential generation and neurotransmitter release.3 Despite attempts to correlate phenotypic severity with functional studies, even within affected kindreds there is *These authors contributed equally to this work.From the

Dominant‐negative mutation p.Arg324Thr in KCNA1 impairs Kv1.1 channel function in episodic ataxia

“…However, the specific functional consequences of mutations do not fully correlate with the clinical phenotype of patients, but instead show phenotypic variability. Thus, mutations in KCNA1 have been identified in a wide phenotypic spectrum, which includes large differences in severity and frequency in EA1 attacks, epilepsy with myokymia, isolated neuromyotonia, persistent cerebellar dysfunction with cognitive delay, and hypomagnesemia among others . Here we report the clinical, genetic, and functional study of KCNA1 /Kv1.1 in a family with EA1 and identify the novel mutation p.Arg324Thr that results in reduced potassium currents and changes in the voltage‐dependence of activation and inactivation.…”

Episodic ataxia type 1 mutations affect fast inactivation of K+ channels by a reduction in either subunit surface expression or affinity for inactivation domain

“…Owing to a noticeable interfamilial and intrafamilial phenotypic variability, genotypeϪphenotype correlation has been extremely difficult to establish reliably (22). Differences in severity and frequency of EA1 attacks have been reported even in identical twins (13).…”

Animal Models of Episodic Ataxia Type 1 (EA1)

“…These results indicated that the degree of impairment of the delayed rectifier function of affected neurons is related to the type and number of mutated subunits that make up the tetrameric Kv1.1 channels (D'Adamo et al, 1998). Coexpression experiments also showed that some mutant subunits exert dominant negative effects on WT subunits, resulting in less than half the normal current, whereas others have virtually no effect (Zerr et al, 1998;D'Adamo et al, 1999;Rea et al, 2002;Imbrici et al, 2006Imbrici et al, , 2011Graves et al, 2010). Kv1.1, Kv1.2, and Kv1.4 are the most abundant subunits expressed in the central nervous system and are assembled to form heteromeric channels composed of Kv1.1/Kv1.2 and Kv1.1/Kv1.4 subunits.…”

“…To date KCNA1 is the only gene known to be associated with EA1, and more than 20 KCNA1 mutations have been identified by sequence analysis, which are distributed throughout the gene (for a review see D'Adamo et al, 2012). Symptom heterogeneity among individuals harboring the same mutation may reflect the interplay of nongenetic factors (Graves et al, 2010). Indeed, even identical twins harboring the same EA1 mutation displayed unexpectedly large differences in the severity and frequency of attacks (Graves et al, 2010).…”

“…Symptom heterogeneity among individuals harboring the same mutation may reflect the interplay of nongenetic factors (Graves et al, 2010). Indeed, even identical twins harboring the same EA1 mutation displayed unexpectedly large differences in the severity and frequency of attacks (Graves et al, 2010).…”