Mutations In KCNA1 Research Articles

Recent advances in the genetics of recurrent vertigo and vestibulopathy

To focus on recent advances in the genetics of recurrent vertigo, with an overview on episodic ataxia, benign recurrent vertigo (mainly migraine-associated vertigo), bilateral vestibulopathy, and Ménière's disease. Since the identification more than a decade ago of the genetic causes of episodic ataxia type 1 with myokymia caused by KCNA1 mutations and episodic ataxia type 2 with nystagmus caused by CACNA1A mutations, the list of episodic ataxia syndromes with distinct clinical features and genetic loci is slowly expanding, now up to episodic ataxia type 7. There is growing recognition for a correlation between benign recurrent vertigo and migraine, and acceptance for vertigo as a manifestation of migraine; efforts to identify susceptibility loci for migraine and migraine-associated vertigo are underway. A handful of families with vestibulopathy spanning several generations have been identified. Although no gene has yet been found, vestibulopathy with normal hearing variably associated with migraine is likely monogenic and heterogeneous, similar to nonsydromic deafness. There is also continuing effort to identify genetic causes of familial Ménière's disease. Overlapping clinical features among different familial syndromes of recurrent vertigo and strong association with migraine suggest shared mechanisms. Collaborative efforts in patient identification and recruitment will facilitate progress in understanding disease mechanisms to improve diagnosis and treatment of recurrent vertigo.

Novel mutation in KCNA1 causes episodic ataxia with paroxysmal dyspnea

Episodic ataxia type 1 (EA1) is an autosomal-dominant neurological disease caused by point mutations in the potassium channel-encoding gene KCNA1. It is characterized by attacks of ataxia and continuous myokymia. Respiratory muscle involvement has not been previously reported in EA1. We clinically evaluated a family with features of EA1 and paroxysmal shortness of breath. Coding and flanking intronic regions of KCNA1 were sequenced. We identified a novel 3-nucleotide deletion mutation in KCNA1 in the affected individuals. Our findings of a deletion mutation with unusual respiratory muscle involvement expand the genetic and clinical spectrum of EA1.

Inherited neuromyotonia: A clinical and genetic study of a family

Neuromyotonia is a disorder of peripheral nerve hyperexcitability characterized by myokymia, muscle cramps and stiffness, delayed muscle relaxation after contraction (pseudomyotonia), and hyperhidrosis, associated with well described spontaneous electromyographic features. It is usually an acquired disorder associated with autoantibodies against neuronal voltage-gated potassium channels. However, mutations of KCNA1, encoding the K + channel subunit hKv1.1, have been reported in rare families with neuromyotonia, and mutations in KCNQ2, encoding voltage-gated potassium M channel subunit, in families with benign neonatal seizures and myokymia. We report a three-generation family with inherited neuromyotonia without evidence of immunological involvement. Genetic study excluded mutations in KCNA1, KCNA2, KCNA6 and KCNQ2 genes. Our study does not completely exclude the involvement of other genes encoding ion channels subunits in the pathogenesis of this disorder. Further studies of familial cases will shed light on the molecular basis of inherited neuromyotonia.

Functional analysis of a novel potassium channel (KCNA1) mutation in hereditary myokymia

Myokymia is characterized by spontaneous, involuntary muscle fiber group contraction visible as vermiform movement of the overlying skin. Myokymia with episodic ataxia is a rare, autosomal dominant trait caused by mutations in KCNA1, encoding a voltage-gated potassium channel. In the present study, we report a family with four members affected with myokymia. Additional clinical features included motor delay initially diagnosed as cerebral palsy, worsening with febrile illness, persistent extensor plantar reflex, and absence of epilepsy or episodic ataxia. Mutation analysis revealed a novel c.676C>A substitution in the potassium channel gene KCNA1, resulting in a T226K nonconservative missense mutation in the Kv1.1 subunit in all affected individuals. Electrophysiological studies of the mutant channel expressed in Xenopus oocytes indicated a loss of function. Co-expression of WT and mutant cRNAs significantly reduced whole-oocyte current compared to expression of WT Kv1.1 alone.

A novel mutation in KCNA1 causes episodic ataxia without myokymia

We describe a unique family in which several individual are affected with episodes of ataxia that best fit the phenotype of episodic ataxia type 2 (EA2). All of the affected family members had episodes typically lasting for several hours, and none of them had muscle abnormalities including myokymia. Episodic ataxia type 1 (EA1) was not considered initially as a clinical diagnosis for the affected individuals in this family. However, by linkage mapping, sequencing and polymorphism analysis, all affecteds were found to have a novel mutation in KCNA1. Numerous missense mutations have been described previously in KCNA1 that cause EA1. The mutation c.1025G>T replaces a highly conserved serine with isoleucine at position 342 (p.Ser342Ile) in the highly conserved fifth transmembrane domain of the KCNA1. This mutation leads to a distinct clinical phenotype without myokymia broadening the scope of clinical characteristics of EA1 and highlighting the heterogeneity of phenotypic effects from distinct missense mutations.

Genetics of familial episodic vertigo and ataxia.

The familial episodic ataxias are prototypical inherited channelopathies that result in episodes of vertigo and ataxia triggered by stress and exercise. Episodic ataxia type 1 (EA-1) is caused by missense mutations in the potassium channel gene KCNA1, whereas episodic ataxia type 2 (EA-2) is caused by missense and nonsense mutations in the calcium channel gene CACNA1A. These ion channels are crucial for both central and peripheral neurotransmission. Within the last few years, the genetic mechanisms underlying these relatively rare familial episodic ataxia syndromes have been worked out. They provide a model for understanding the mechanisms of more common recurrent vertigo and ataxia syndromes, particularly those associated with migraine. Migraine affects as many as 15-20% of the general population, and it has been estimated that about 25% of patients with migraine experience spontaneous attacks of vertigo and ataxia. We identified 24 families with migraine and benign recurrent vertigo inherited in an autosomal dominant fashion. These families have numerous features in common with EA-1 and EA-2 (particularly EA-2), suggesting that benign recurrent vertigo may be an inherited channelopathy. An ion channel mutation shared by brain and inner ear could explain the combined central and peripheral features of the syndrome.

Variable K(+) channel subunit dysfunction in inherited mutations of KCNA1.

Mutations of KCNA1, which codes for the K(+) channel subunit hKv1.1, are associated with the human autosomal dominant disease episodic ataxia type 1 (EA1). Five recently described mutations are associated with a broad range of phenotypes: neuromyotonia alone or with seizures, EA1 with seizures, or very drug-resistant EA1. Here we investigated the consequences of each mutation for channel assembly, trafficking, gating and permeation. We related data obtained from co-expression of mutant and wild-type hKv1.1 to the results of expressing mutant-wild-type fusion proteins, and combined electrophysiological recordings in Xenopus oocytes with a pharmacological discrimination of the contribution of mutant and wild-type subunits to channels expressed at the membrane. We also applied confocal laser scanning microscopy to measure the level of expression of either wild-type or mutant subunits tagged with green fluorescent protein (GFP). R417stop truncates most of the C-terminus and is associated with severe drug-resistant EA1. Electrophysiological and pharmacological measurements indicated that the mutation impairs both tetramerisation of R417stop with wild-type subunits, and membrane targeting of heterotetramers. This conclusion was supported by confocal laser scanning imaging of enhanced GFP (EGFP)-tagged hKv1.1 subunits. Co-expression of R417stop with wild-type hKv1.2 subunits yielded similar results to co-expression with wild-type hKv1.1. Mutations associated with typical EA1 (V404I) or with neuromyotonia alone (P244H) significantly affected neither tetramerisation nor trafficking, and only altered channel kinetics. Two other mutations associated with a severe phenotype (T226R, A242P) yielded an intermediate result. The phenotypic variability of KCNA1 mutations is reflected in a wide range of disorders of channel assembly, trafficking and kinetics.

Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability

Episodic ataxia type 1 (EA1) is an autosomal dominant central nervous system potassium channelopathy characterized by brief attacks of cerebellar ataxia and continuous interictal myokymia. Point mutations in the voltage-gated potassium channel gene KCNA1 on chromosome 12p associate with EA1. We have studied 4 families and identified three new and one previously reported heterozygous point mutations in this gene. Affected members in Family A (KCNA1 G724C) exhibit partial epilepsy and myokymia but no ataxic episodes, supporting the suggestion that there is an association between mutations of KCNA1 and epilepsy. Affected members in Family B (KCNA1 C731A) exhibit myokymia alone, suggesting a new phenotype of isolated myokymia. Family C harbors the first truncation to be reported in KCNA1 (C1249T) and exhibits remarkably drug-resistant EA1. Affected members in Family D (KCNA1 G1210A) exhibit attacks typical of EA1. This mutation has recently been reported in an apparently unrelated family, although no functional studies were attempted. Heterologous expression of the proteins encoded by the mutant KCNA1 genes suggest that the four point mutations impair delayed-rectifier type potassium currents by different mechanisms. Increased neuronal excitability is likely to be the common pathophysiological basis for the disease in these families. The degree and nature of the potassium channel dysfunction may be relevant to the new phenotypic observations reported in this study. Ann Neurol 2000;48:647–656

Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability

Episodic ataxia type 1 (EA1) is an autosomal dominant central nervous system potassium channelopathy characterized by brief attacks of cerebellar ataxia and continuous interictal myokymia. Point mutations in the voltage-gated potassium channel gene KCNA1 on chromosome 12p associate with EA1. We have studied 4 families and identified three new and one previously reported heterozygous point mutations in this gene. Affected members in Family A (KCNA1 G724C) exhibit partial epilepsy and myokymia but no ataxic episodes, supporting the suggestion that there is an association between mutations of KCNA1 and epilepsy. Affected members in Family B (KCNA1 C731A) exhibit myokymia alone, suggesting a new phenotype of isolated myokymia. Family C harbors the first truncation to be reported in KCNA1 (C1249T) and exhibits remarkably drug-resistant EA1. Affected members in Family D (KCNA1 G1210A) exhibit attacks typical of EA1. This mutation has recently been reported in an apparently unrelated family, although no functional studies were attempted. Heterologous expression of the proteins encoded by the mutant KCNA1 genes suggest that the four point mutations impair delayed-rectifier type potassium currents by different mechanisms. Increased neuronal excitability is likely to be the common pathophysiological basis for the disease in these families. The degree and nature of the potassium channel dysfunction may be relevant to the new phenotypic observations reported in this study.

Functional characterization of a novel mutation in KCNA1 in episodic ataxia type 1 associated with epilepsy.

Annals of the New York Academy of SciencesVolume 868, Issue 1 p. 442-446 Functional Characterization of a Novel Mutation in KCNA1 in Episodic Ataxia Type 1 Associated with Epilepsy ALEXANDER SPAUSCHUS, Corresponding Author ALEXANDER SPAUSCHUS University Department of Clinical Neurology, Institute of Neurology/UCL, Queen Square, London WC1N 3BG, United Kingdom Corresponding author. Phone: +44-171-837 3611 extension 4181; fax: +44-171-278 5616; e-mail: A.Spauschus@ion.ucl.ac.ukSearch for more papers by this authorLOUISE EUNSON, LOUISE EUNSON University Department of Clinical Neurology, Institute of Neurology/UCL, Queen Square, London WC1N 3BG, United KingdomSearch for more papers by this authorMICHAEL G. HANNA, MICHAEL G. HANNA University Department of Clinical Neurology, Institute of Neurology/UCL, Queen Square, London WC1N 3BG, United KingdomSearch for more papers by this authorDIMITRI M. KULLMANN, DIMITRI M. KULLMANN University Department of Clinical Neurology, Institute of Neurology/UCL, Queen Square, London WC1N 3BG, United KingdomSearch for more papers by this author ALEXANDER SPAUSCHUS, Corresponding Author ALEXANDER SPAUSCHUS University Department of Clinical Neurology, Institute of Neurology/UCL, Queen Square, London WC1N 3BG, United Kingdom Corresponding author. Phone: +44-171-837 3611 extension 4181; fax: +44-171-278 5616; e-mail: A.Spauschus@ion.ucl.ac.ukSearch for more papers by this authorLOUISE EUNSON, LOUISE EUNSON University Department of Clinical Neurology, Institute of Neurology/UCL, Queen Square, London WC1N 3BG, United KingdomSearch for more papers by this authorMICHAEL G. HANNA, MICHAEL G. HANNA University Department of Clinical Neurology, Institute of Neurology/UCL, Queen Square, London WC1N 3BG, United KingdomSearch for more papers by this authorDIMITRI M. KULLMANN, DIMITRI M. KULLMANN University Department of Clinical Neurology, Institute of Neurology/UCL, Queen Square, London WC1N 3BG, United KingdomSearch for more papers by this author First published: 06 February 2006 https://doi.org/10.1111/j.1749-6632.1999.tb11310.xCitations: 22Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume868, Issue1MOLECULAR AND FUNCTIONAL DIVERSITY OF ION CHANNELS AND RECEPTORSApril 1999Pages 442-446 RelatedInformation

Three novel KCNA1 mutations in episodic ataxia type I families.

Hereditary paroxysmal ataxia, or episodic ataxia (EA), is a rare, genetically heterogeneous neurological disorder characterized by attacks of generalized ataxia. By direct sequence analysis, a different missense mutation of the potassium channel gene (KCNA1) has been identified in three families with EA.

Identification of two new KCNA1 mutations in episodic ataxia/myokymia families.

Identification of two new KCNA1 mutations in episodic ataxia/myokymia families.