Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since 1990, many mutations, in genes encoding ion channels have been discovered to cause disorders characterized by hyper- or hypoexcitability of skeletal muscle or the central nervous system (CNS): i) mutations in the muscle chloride channel gene lead to a loss or change of function of the channels and cause an abnormally low total chloride conductance resulting in hyperexcitability of the muscle fiber membrane in the dominant and recessive form of myotonia congenita; ii) numerous dominant point mutations in the gene encoding the muscle sodium channel alpha-subunit cause incomplete sodium channel inactivation. Dependent on the inactivation parameter altered and the degree of the gain of function induced by a given mutation, the muscle episodically becomes hyper- or hypoexcitable (i.e. stiff or weak), particularly in response to elevated serum potassium (potassium-aggravated myotonia, hyperkalemic periodic paralysis) or cold environment (paramyotonia congenita); iii) dominant point mutations in the gene coding for the muscle L-type calcium channel alpha(1)-subunit can cause episodes of muscle inexcitability (i.e. weakness), particularly in response to lowered serum potassium (hypokalemic periodic paralysis); despite the recently discovered etiology of the disease, the pathogenesis of the weakness is still unknown; iv) dominant mutations in a voltage-gated potassium channel expressed in the CNS cause episodic ataxia type 1 presumably by antagonizing repolarization of the cell membrane; v) dominant mutations in a neuronal calcium channel alpha-subunit may cause either episodic ataxia type II or familial hemiplegic migraine by a so far unknown pathomechanism; vi) the first mutation in an ion channel associated with an inherited form of epilepsy, nocturnal frontal lobe epilepsy, was found in the alpha(4)-subunit of a neuronal nicotinic acetylcholine receptor.
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PMID:[Ion channel diseases in neurology]. 948 Feb 90

Subunits of the voltage-gated potassium channel Kv1.1 containing mutations responsible for episodic ataxia (EA), a human inherited neurological disease, were expressed in Xenopus oocytes. Five EA subunits formed functional homomeric channels with lower current amplitudes and altered gating properties compared with wild type. Two EA mutations located in the first cytoplasmic loop, R239S and F249I, yielded minimal or no detectable current, and Western blot analysis showed reduced protein levels. Coinjection of equal amounts of EA and wild-type mRNAs, mimicking the heterozygous condition, resulted in current amplitudes and gating properties that were intermediate between wild-type and EA homomeric channels, suggesting that heteromeric channels are formed with a mixed stoichiometry of EA and wild-type subunits. To examine the relative contribution of EA subunits in forming heteromeric EA and wild-type channels, each EA subunit was made insensitive to TEA, TEA-tagged, and coexpressed with wild-type subunits. TEA-tagged R239S and F249I induced the smallest shift in TEA sensitivity compared with homomeric wild-type channels, whereas the other TEA-tagged EA subunits yielded TEA sensitivities similar to coexpression of wild-type and TEA-tagged wild-type subunits. Taken together, these results show that the different mutations in Kv1.1 affect channel function and indicate that both dominant negative effects and haplotype insufficiency may result in the symptoms of EA.
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PMID:Episodic ataxia mutations in Kv1.1 alter potassium channel function by dominant negative effects or haploinsufficiency. 952 1

Mice lacking the voltage-gated potassium channel alpha subunit, K(V)1.1, display frequent spontaneous seizures throughout adult life. In hippocampal slices from homozygous K(V)1.1 null animals, intrinsic passive properties of CA3 pyramidal cells are normal. However, antidromic action potentials are recruited at lower thresholds in K(V)1.1 null slices. Furthermore, in a subset of slices, mossy fiber stimulation triggers synaptically mediated long-latency epileptiform burst discharges. These data indicate that loss of K(V)1.1 from its normal localization in axons and terminals of the CA3 region results in increased excitability in the CA3 recurrent axon collateral system, perhaps contributing to the limbic and tonic-clonic components of the observed epileptic phenotype. Axonal action potential conduction was altered as well in the sciatic nerve--a deficit potentially related to the pathophysiology of episodic ataxia/myokymia, a disease associated with missense mutations of the human K(V)1.1 gene.
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PMID:Deletion of the K(V)1.1 potassium channel causes epilepsy in mice. 958 71

Episodic ataxia type 1 (EA1) is a rare autosomal dominant disorder characterized by brief episodes of ataxia associated with continuous interattack myokymia. Point mutations in the human voltage-gated potassium channel (Kv1.1) gene on chromosome 12p13 have recently been shown to associate with EA1. A Scottish family with EA1 harbouring a novel mutation in this gene is reported. Of the five affected individuals over three generations, two had partial epilepsy in addition to EA1. The detailed clinical, electrophysiological and molecular genetic findings are presented. The heterozygous point mutation is located at nucleotide position 677 and results in a radical amino acid substitution at a highly conserved position in the second transmembrane domain of the potassium channel. Functional studies indicated that mutant subunits exhibited a dominant negative effect on potassium channel function and would be predicted to impair neuronal repolarization. Potassium channels determine the excitability of neurons and blocking drugs are proconvulsant. A critical review of previously reported EA1 families shows an over-representation of epilepsy in family members with EA1 compared with unaffected members. These observations indicate that this mutation is pathogenic and suggest that the epilepsy in EA1 may be caused by the dysfunctional potassium channel. It is possible that such dysfunction may be relevant to other epilepsies in man.
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PMID:A novel mutation in the human voltage-gated potassium channel gene (Kv1.1) associates with episodic ataxia type 1 and sometimes with partial epilepsy. 1035 68

Episodic ataxia type-1 syndrome (EA-1) is an autosomal dominant neurological disorder that manifests itself during infancy and results from point mutations in the voltage-gated potassium channel gene hKv1.1. The hallmark of the disease is continuous myokymia and episodic attacks of spastic contractions of the skeletal muscles, which cause permanent disability. Coexpression of hKv1.1 and hKv1.2 subunits produces heteromeric potassium channels with biophysical and pharmacological properties intermediate between the respective homomers. By using tandemly linked subunits, we demonstrate that hKv1.1 subunits bearing the EA-1 mutations V408A and E325D combine with hKv1.2 to produce channels with altered kinetics of activation, deactivation, C-type inactivation, and voltage dependence. Moreover, hKv1.1V408A single-channel analysis reveals a approximately threefold reduction of the mean open duration of the channel compared with the wild-type, and this mutation alters the open-state stability of both homomeric and heteromeric channels. The results demonstrate that human Kv1.2 and Kv1.1 subunits coassemble to form a novel channel with distinct gating properties that are altered profoundly by EA-1 mutations, thus uncovering novel physiopathogenetic mechanisms of episodic ataxia type-1 myokymia syndrome.
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PMID:Mutations in the KCNA1 gene associated with episodic ataxia type-1 syndrome impair heteromeric voltage-gated K(+) channel function. 1042 58

Ion channels provide the basis for the regulation of excitability in the central nervous system and in other excitable tissues such as skeletal and heart muscle. Consequently, mutations in ion channel encoding genes are found in a variety of inherited diseases associated with hyper- or hypoexcitability of the affected tissue, the so-called 'channelopathies.' An increasing number of epileptic syndromes belongs to this group of rare disorders: Autosomal dominant nocturnal frontal lobe epilepsy is caused by mutations in a neuronal nicotinic acetylcholine receptor (affected genes: CHRNA4, CHRNB2), benign familial neonatal convulsions by mutations in potassium channels constituting the M-current (KCNQ2, KCNQ3), generalized epilepsy with febrile seizures plus by mutations in subunits of the voltage-gated sodium channel or the GABA(A) receptor (SCN1B, SCN1A, GABRG2), and episodic ataxia type 1-which is associated with epilepsy in a few patients--by mutations within another voltage-gated potassium channel (KCNA1). These rare disorders provide interesting models to study the etiology and pathophysiology of disturbed excitability in molecular detail. On the basis of genetic and electrophysiologic studies of the channelopathies, novel therapeutic strategies can be developed, as has been shown recently for the antiepileptic drug retigabine activating neuronal KCNQ potassium channels.
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PMID:Ion channels and epilepsy. 1157 35

Episodic ataxia type-1 (EA1) is a dominant human neurological disorder characterized by stress-induced attacks of ataxia. EA1 is caused by mutations in the voltage-gated potassium channel Kv1.1, and affected individuals are heterozygous. Here we introduced the V408A EA1 mutation into mice using homologous recombination. In contrast to Kv1.1 null mice, homozygous V408A/V408A mice died after embryonic day 3 (E3). V408A/+ mice showed stress-induced loss of motor coordination that was ameliorated by acetazolamide, a carbonic anhydrase inhibitor that minimizes EA1 symptoms in human patients. We made electrophysiological recordings from cerebellar Purkinje cells in both V408A/+ mice and their wild-type littermates. V408A/+ mice showed a greater frequency and amplitude of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) than did wild type; however, the amplitude or frequency of miniature IPSCs and the basket cell firing frequency did not differ between groups. The stress-induced motor dysfunction in V408A mice is similar to that of family members harboring the EA1 allele, and our findings suggest that these behavioral changes are linked to changes in GABA release.
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PMID:A mouse model of episodic ataxia type-1. 1261 86

Episodic ataxia type1 (EA1) is an autosomal dominant disorder characterised by episodes of ataxia, dysarthria, tremor and visual disturbances lasting for seconds or minutes, precipitated by physical and emotional stress, startle or sudden movements. In addition there is continuous myokymia. Phenotypic variants such as the combination with epilepsy, shortening of the Achilles tendon in children, transient postural abnormalities in infancy, and a very few patients with longer lasting episodes have been reported. We describe a 10-year-old girl with EA1 who has distal weakness with paresis of the extensors of the feet and prolonged spells of limb stiffness (neuromyotonia) lasting up to 12 hours. A novel single nucleotide change at position 785 T > C that alters a highly conserved residue in the third transmembrane segment of the voltage-gated potassium channel Kv1.1 was found.
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PMID:Episodic ataxia type 1 with distal weakness: a novel manifestation of a potassium channelopathy. 1512 17

We report an unusual family in which the same point mutation in the voltage-gated potassium channel gene KCNA1 resulted in markedly different clinical phenotypes. The propositus presented in infancy with marked muscle stiffness, motor developmental delay, short stature, skeletal deformities, muscle hypertrophy and muscle rippling on percussion. He did not experience episodic ataxia. His mother presented some years later with typical features of Episodic Ataxia type 1 (EA1), with episodes of ataxia lasting a few minutes provoked by exercise. On examination she had myokymia, joint contractures and mild skeletal deformities. A heterozygous point mutation in the voltage-gated K(+) channel (KCNA1) gene (ACG-AGG, Thr226Arg) was found in both. We conclude that mutations in the potassium channel gene (KCNA1) can cause severe neuromyotonia resulting in marked skeletal deformities even if episodic ataxia is not prominent.
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PMID:Expanding the phenotype of potassium channelopathy: severe neuromyotonia and skeletal deformities without prominent Episodic Ataxia. 1535 27

Episodic ataxia type-1 (EA1) is a human neurological syndrome characterized by attacks of generalized ataxia and by continuous myokymia that has been associated with point mutations in the voltage-gated potassium channel gene KCNA1. Although important advancement has been made in understanding the molecular pathophysiology of EA1, several disease-causing mechanisms remain poorly understood. F184C is an EA1 mutation that is located within the S1 segment of the human Kv1.1 subunit. Here, we show that the F184C mutation increases approximately 4.5-fold the sensitivity of the channel to extracellular Zn2+. Both Zn2+and Cd2+ markedly alter the activation kinetics of F184C channel. In addition, the mutated channel reacts with several methane thiosulfonate reagents which specifically affected channel function. The results provide structural implications and indicate that sensitisation of hKv1.1 to Zn2+ is likely to contribute to the EA1 symptoms in patients harboring the F184C mutation.
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PMID:An episodic ataxia type-1 mutation in the S1 segment sensitises the hKv1.1 potassium channel to extracellular Zn2+. 1547 44


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