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M.G. Hanna - One of the best experts on this subject based on the ideXlab platform.
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Nerve excitability studies characterize K(V)1.1 fast potassium channel dysfunction in patients with Episodic Ataxia type 1
OXFORD UNIV PRESS, 2010Co-Authors: Se Tomlinson, M.G. Hanna, Dimitri M Kullmann, Sv Tan, Rc Griggs, Burke D, Bostock HAbstract:Episodic Ataxia type 1 is a neuronal channelopathy caused by mutations in the KCNA1 gene encoding the fast K+ channel subunit K(v)1.1. Episodic Ataxia type 1 presents with brief episodes of cerebellar dysfunction and persistent neuromyotonia and is associated with an increased incidence of epilepsy. In myelinated peripheral nerve, Kv1.1 is highly expressed in the juxtaparanodal axon, where potassium channels limit the depolarizing afterpotential and the effects of depolarizing currents. Axonal excitability studies were performed on patients with genetically confirmed Episodic Ataxia type 1 to characterize the effects of Kv1.1 dysfunction on motor axons in vivo. The median nerve was stimulated at the wrist and compound muscle action potentials were recorded from abductor pollicis brevis. Threshold tracking techniques were used to record strength-duration time constant, threshold electrotonus, current/threshold relationship and the recovery cycle. Recordings from 20 patients from eight kindreds with different KCNA1 point mutations were compared with those from 30 normal controls. All 20 patients had a history of Episodic Ataxia and 19 had neuromyotonia. All patients had similar, distinctive abnormalities: superexcitability was on average 100% higher in the patients than in controls (P < 0.00001) and, in threshold electrotonus, the increase in excitability due to a depolarizing current (20% of threshold) was 31% higher (P < 0.00001). Using these two parameters, the patients with Episodic Ataxia type 1 and controls could be clearly separated into two non-overlapping groups. Differences between the different KCNA1 mutations were not statistically significant. Studies of nerve excitability can identify Kv1.1 dysfunction in patients with Episodic Ataxia type 1. The simple 15 min test may be useful in diagnosis, since it can differentiate patients with Episodic Ataxia type 1 from normal controls with high sensitivity and specificity
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premature stop codons in a facilitating ef hand splice variant of cav2 1 cause Episodic Ataxia type 2
Neurobiology of Disease, 2008Co-Authors: Tracey D. Graves, L H Eunson, Paola Imbrici, E E Kors, Gisela M Terwindt, J Haan, R R Frants, Michel D Ferrari, Peter J Goadsby, M.G. HannaAbstract:Abstract Premature stop codons in CACNA1A , which encodes the α 1A subunit of neuronal P/Q-type (Ca V 2.1) Ca 2+ channels, cause Episodic Ataxia type 2 (EA2). CACNA1A undergoes extensive alternative splicing, which contributes to the pharmacological and kinetic heterogeneity of Ca V 2.1-mediated Ca 2+ currents. We identified three novel heterozygous stop codon mutations associated with EA2 in an alternately spliced exon (37A), which encodes part of an EF-hand motif required for Ca 2+ -dependent facilitation. One family had a C to G transversion (Y1854X). A dinucleotide deletion results in the same premature stop codon in a second family, and a further single nucleotide change leads to a different truncation (R1858X) in a de novo case of EA2. Expression studies of the Y1854X mutation revealed loss of Ca V 2.1-mediated current. Because these mutations do not affect the alternate exon 37B, these findings reveal unexpected dependence of cerebellar function on intact exon 37A-containing Ca V 2.1 channels.
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New calcium channel mutations predict aberrant RNA splicing in Episodic Ataxia
2005Co-Authors: L H Eunson, Td Graves, M.G. HannaAbstract:Episodic Ataxia type 2 (EA2) is an autosomal dominant channelopathy characterized by paroxysmal cerebellar Ataxia. Previous studies suggest that most EA2 cases are associated with mutations in the α1Asubunit of the P/Q-type voltage-gated calcium channel gene CACNA1A. In a UK national study, the authors analyzed 15 index cases with typical EA2 and identified two unreported intronic mutations that predict aberrant splicing. Copyright © 2005 by AAN Enterprises, Inc
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New calcium channel mutations predict aberrant RNA splicing in Episodic Ataxia
NEUROLOGY, 2005Co-Authors: M.G. HannaAbstract:Episodic Ataxia type 2 (EA2) is an autosomal dominant channelopathy characterized by paroxysmal cerebellar Ataxia. Previous studies suggest that most EA2 cases are associated with mutations in the alpha(1A) subunit of the P/Q-type voltage-gated calcium channel gene CACNA1A. In a UK national study, the authors analyzed 15 index cases with typical EA2 and identified two unreported intronic mutations that predict aberrant splicing.
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Late-onset Episodic Ataxia type 2 due to an in-frame insertion in CACNA1A
NEUROLOGY, 2005Co-Authors: M.G. HannaAbstract:Episodic Ataxia type 2 (EA2) is caused by calcium channel (CACNA1A) mutations and typically begins before age 20 years. The molecular basis of late-onset EA2 is unclear. The authors describe a case of late-onset EA2 associated with the first multiple-base pair insertion in CACNA1A. Molecular expression revealed evidence of impaired calcium channel function, suggesting that genetically induced reduction in calcium channel function may associate with cases of late-onset EA2.
Robert W Baloh - One of the best experts on this subject based on the ideXlab platform.
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Episodic Ataxia type 1: clinical characterization, quality of life and genotype-phenotype correlation
Brain, 2014Co-Authors: Tracey D. Graves, Robert W Baloh, Joanna C. Jen, Yoon-hee Cha, A. F. Hahn, Richard J. Barohn, Mohammed K. Salajegheh, Robert C. Griggs, Brian N. Bundy, Michael G. HannaAbstract:Episodic Ataxia type 1 is considered a rare neuronal ion channel disorder characterized by brief attacks of unsteadiness and dizziness with persistent myokymia. To characterize the natural history, develop outcome measures for future clinical trials, and correlate genotype with phenotype, we undertook an international, prospective, cross-sectional study. Thirty-nine individuals (51% male) were enrolled: median age 37 years (range 15–65 years). We identified 10 different pathogenic point mutations in KCNA1 that accounted for the genetic basis of 85% of the cohort. Participants with KCNA1 mutations were more likely to have a positive family history. Analysis of the total cohort showed that the first episode of Ataxia occurred before age 20 in all but one patient, with an average age of onset of 7.9 years. Physical exertion, emotional stress and environmental temperature were the most common triggers for attacks. Attack frequency ranged from daily to monthly, even with the same KCNA1 genotype. Average attack duration was in the order of minutes. Ten participants (26%) developed permanent cerebellar signs, which were related to disease duration. The average Scale for the Assessment and Rating of Ataxia score (SARA, a standardized measure of cerebellar dysfunction on clinical examination, scores range from 0–40) was an average of 3.15 for all participants (range 0–14), but was only 2 in those with isolated Episodic Ataxia compared with 7.7 in those with progressive cerebellar Ataxia in addition to Episodic Ataxia. Thirty-seven participants completed the SF-36, a quality of life survey; all eight domain norm-based average scores (mean = 50) were below normal with mental health being the lowest (41.3) in those with mutation positive Episodic Ataxia type 1. Scores on SF-36 correlated negatively with attack frequency. Of the 39 participants in the study, 33 harboured mutations in KCNA1 whereas the remaining six had no mutation identified. Episodic Ataxia type 1 phenocopies have not been described previously and we report their clinical features, which appear to be different to those with a KCNA1 mutation. This large prospective study of both genetically confirmed Episodic Ataxia type 1 and Episodic Ataxia type 1 phenocopies provides detailed baseline characteristics of these disorders and their impact on participants. We found that attacks had a significant effect on quality of life. Unlike previous studies, we found that a significant number of individuals with genetically confirmed Episodic Ataxia type 1 (21%) had accumulated persistent cerebellar symptoms and signs. These data will enable the development of outcome measures for clinical trials of treatment.
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large genomic deletions in cacna1a cause Episodic Ataxia type 2
Frontiers in Neurology, 2011Co-Authors: Jijun Wan, Hafsa Mamsa, Robert W Baloh, Janine L Johnston, Elizabeth Spriggs, Harvey S Singer, David S Zee, Alhamza R Albayati, Joanna C. JenAbstract:Episodic Ataxia (EA) syndromes are heritable diseases characterized by dramatic episodes of imbalance and incoordination. EA type 2 (EA2), the most common and the best characterized subtype, is caused by mostly nonsense, splice site, small indel, and sometimes missense mutations in CACNA1A. Direct sequencing of CACNA1A fails to identify mutations in some patients with EA2-like features, possibly due to incomplete interrogation of CACNA1A or defects in other EA genes not yet defined. Previous reports described genomic deletions between 4 and 40 kb in EA2. In 47 subjects with EA (26 with EA2-like features) who tested negative for mutations in the known EA genes, we used multiplex ligation-dependent probe amplification to analyze CACNA1A for exonic copy number variations. Breakpoints were further defined by long-range PCR. We identified distinct multi-exonic deletions in three probands with classic EA2-like features: episodes of prolonged vertigo and Ataxia triggered by stress and fatigue, interictal nystagmus, with onset during infancy or early childhood. The breakpoints in all three probands are located in Alu sequences, indicating errors in homologous recombination of Alu sequences as the underlying mechanism. The smallest deletion spanned exons 39 and 40, while the largest deletion spanned 200 kb, missing all but the first three exons. One deletion involving exons 39 through 47 arose spontaneously. The search for mutations in CACNA1A appears most fruitful in EA patients with interictal nystagmus and onset early in life. The finding of large heterozygous deletions suggests haploinsufficiency as a possible pathomechanism of EA2.
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novel mutation in kcna1 causes Episodic Ataxia with paroxysmal dyspnea
Muscle & Nerve, 2008Co-Authors: Steven J Shook, Hafsa Mamsa, Robert W Baloh, Lan ZhouAbstract: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. Muscle Nerve, 2007
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mutation in the glutamate transporter eaat1 causes Episodic Ataxia hemiplegia and seizures
Neurology, 2005Co-Authors: Joanna Jen, Jijun Wan, T P Palos, B D Howard, Robert W BalohAbstract:Background: Transporters, ion pumps, and ion channels are membrane proteins that regulate selective permeability and maintain ionic gradients across cell membranes. Mutations in CACNA1A encoding a neuronal calcium channel and ATP1A2 encoding an ion pump cause Episodic Ataxia, hemiplegic migraine, and seizures. Mutant gene products of both CACNA1A and ATP1A2 may affect neurotransmission of glutamate, the most abundant excitatory amino acid neurotransmitter. Methods: We examined our patient population with Episodic Ataxia and hemiplegic migraine but with no mutation in either CACNA1A or ATP1A2. We looked for mutations in SLC1A3 , which encodes the glutamate transporter excitatory amino acid transporter (EAAT) 1 that is important in removing glutamate from the synaptic cleft. Results: A patient with Episodic Ataxia, seizures, migraine, and alternating hemiplegia has a heterozygous mutation in SLC1A3 that is not present in his asymptomatic parents and controls. Expression studies of the mutant EAAT1 showed decreased expression of the protein with a markedly reduced capacity for glutamate uptake. When coexpressed, the mutant EAAT1 decreased the activity of wild-type EAAT1 but not of two other transporters EAAT2 or EAAT3, suggesting that mutant EAAT1 specifically multimerizes with wild-type EAAT1 to exert its dominant negative effect. Conclusion: Our data show that a heterozygous mutation in EAAT1 can lead to decreased glutamate uptake, which can contribute to neuronal hyperexcitability to cause seizures, hemiplegia, and Episodic Ataxia.
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Internuclear Ophthalmoparesis in Episodic Ataxia Type 2
Annals of the New York Academy of Sciences, 2005Co-Authors: Janet C. Rucker, Robert W Baloh, Joanna Jen, John S. Stahl, Nandhitha Natesan, R. John LeighAbstract:Two patients sharing a novel mutation of the CACNA1A gene for P/Q calcium channels showed significant slowing of adducting saccades compared with normal subjects or patients with cerebellar disease. Internuclear ophthalmoparesis (INO) was clinically evident in one. While these findings might be specific to this mutation, INO in our patients with Episodic Ataxia type 2 suggested involvement outside the cerebellum, either in the brain-stem internuclear pathway or at the neuromuscular junction.
Joanna C. Jen - One of the best experts on this subject based on the ideXlab platform.
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late onset Episodic Ataxia associated with slc1a3 mutation
Journal of Human Genetics, 2017Co-Authors: Joanna C. Jen, Hyo Jung Kim, Ji Soo Kim, Jin Hong Shin, Seo Young Choi, Hyangsook Kim, Jae-hwan ChoiAbstract:Episodic Ataxia type 6 (EA6) is caused by mutations in SLC1A3 that encodes excitatory amino acid transporter 1 (EAAT1), a glial glutamate transporter. EAAT1 regulates the extent and durations of glutamate-mediated signal by the clearance of glutamate after synaptic release. In addition, EAAT1 also has an anion channel activity that prevents additional glutamate release. We identified a missense mutation in SLC1A3 in a family with EA. The proband exhibited typical EA2-like symptoms such as recurrent Ataxia, slurred speech with a duration of several hours, interictal nystagmus and response to acetazolamide, but had late-onset age of sixth decade. Whole-exome sequencing detected a heterozygous c.1177G>A mutation in SLC1A3. This mutation predicted a substitution of isoleucine for a highly conserved valine residue in the seventh transmembrane domain of EAAT1. The mutation was not present in 100 controls, a large panel of in-house genome data and various mutation databases. Most functional prediction scores revealed to be deleterious. Same heterozygous mutation was identified in one clinically affected family member and two asymptomatic members. Our data expand the mutation spectrum of SLC1A3 and the clinical phenotype of EA6.
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Episodic Ataxia type 1: clinical characterization, quality of life and genotype-phenotype correlation
Brain, 2014Co-Authors: Tracey D. Graves, Robert W Baloh, Joanna C. Jen, Yoon-hee Cha, A. F. Hahn, Richard J. Barohn, Mohammed K. Salajegheh, Robert C. Griggs, Brian N. Bundy, Michael G. HannaAbstract:Episodic Ataxia type 1 is considered a rare neuronal ion channel disorder characterized by brief attacks of unsteadiness and dizziness with persistent myokymia. To characterize the natural history, develop outcome measures for future clinical trials, and correlate genotype with phenotype, we undertook an international, prospective, cross-sectional study. Thirty-nine individuals (51% male) were enrolled: median age 37 years (range 15–65 years). We identified 10 different pathogenic point mutations in KCNA1 that accounted for the genetic basis of 85% of the cohort. Participants with KCNA1 mutations were more likely to have a positive family history. Analysis of the total cohort showed that the first episode of Ataxia occurred before age 20 in all but one patient, with an average age of onset of 7.9 years. Physical exertion, emotional stress and environmental temperature were the most common triggers for attacks. Attack frequency ranged from daily to monthly, even with the same KCNA1 genotype. Average attack duration was in the order of minutes. Ten participants (26%) developed permanent cerebellar signs, which were related to disease duration. The average Scale for the Assessment and Rating of Ataxia score (SARA, a standardized measure of cerebellar dysfunction on clinical examination, scores range from 0–40) was an average of 3.15 for all participants (range 0–14), but was only 2 in those with isolated Episodic Ataxia compared with 7.7 in those with progressive cerebellar Ataxia in addition to Episodic Ataxia. Thirty-seven participants completed the SF-36, a quality of life survey; all eight domain norm-based average scores (mean = 50) were below normal with mental health being the lowest (41.3) in those with mutation positive Episodic Ataxia type 1. Scores on SF-36 correlated negatively with attack frequency. Of the 39 participants in the study, 33 harboured mutations in KCNA1 whereas the remaining six had no mutation identified. Episodic Ataxia type 1 phenocopies have not been described previously and we report their clinical features, which appear to be different to those with a KCNA1 mutation. This large prospective study of both genetically confirmed Episodic Ataxia type 1 and Episodic Ataxia type 1 phenocopies provides detailed baseline characteristics of these disorders and their impact on participants. We found that attacks had a significant effect on quality of life. Unlike previous studies, we found that a significant number of individuals with genetically confirmed Episodic Ataxia type 1 (21%) had accumulated persistent cerebellar symptoms and signs. These data will enable the development of outcome measures for clinical trials of treatment.
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large genomic deletions in cacna1a cause Episodic Ataxia type 2
Frontiers in Neurology, 2011Co-Authors: Jijun Wan, Hafsa Mamsa, Robert W Baloh, Janine L Johnston, Elizabeth Spriggs, Harvey S Singer, David S Zee, Alhamza R Albayati, Joanna C. JenAbstract:Episodic Ataxia (EA) syndromes are heritable diseases characterized by dramatic episodes of imbalance and incoordination. EA type 2 (EA2), the most common and the best characterized subtype, is caused by mostly nonsense, splice site, small indel, and sometimes missense mutations in CACNA1A. Direct sequencing of CACNA1A fails to identify mutations in some patients with EA2-like features, possibly due to incomplete interrogation of CACNA1A or defects in other EA genes not yet defined. Previous reports described genomic deletions between 4 and 40 kb in EA2. In 47 subjects with EA (26 with EA2-like features) who tested negative for mutations in the known EA genes, we used multiplex ligation-dependent probe amplification to analyze CACNA1A for exonic copy number variations. Breakpoints were further defined by long-range PCR. We identified distinct multi-exonic deletions in three probands with classic EA2-like features: episodes of prolonged vertigo and Ataxia triggered by stress and fatigue, interictal nystagmus, with onset during infancy or early childhood. The breakpoints in all three probands are located in Alu sequences, indicating errors in homologous recombination of Alu sequences as the underlying mechanism. The smallest deletion spanned exons 39 and 40, while the largest deletion spanned 200 kb, missing all but the first three exons. One deletion involving exons 39 through 47 arose spontaneously. The search for mutations in CACNA1A appears most fruitful in EA patients with interictal nystagmus and onset early in life. The finding of large heterozygous deletions suggests haploinsufficiency as a possible pathomechanism of EA2.
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clinical spectrum of Episodic Ataxia type 2
Neurology, 2004Co-Authors: Joanna C. Jen, Gilbert W Kim, Robert W BalohAbstract:The authors searched for mutations in CACNA1A in patients with Episodic Ataxia and describe the clinical spectrum in genetically defined patients. Eighteen families and nine sporadic cases of Episodic Ataxia were evaluated for mutations in CACNA1A . The families were first genotyped to check for linkage to the chromosome 19p locus of CACNA1A . In families consistent with linkage and in the sporadic cases, the authors screened for polymorphisms in CACNA1A using single-strand conformational polymorphism and denaturing high performance liquid chromatography followed by direct sequencing to identify specific nucleotide changes. Of the 18 families, 11 were linked to 19p and mutations were found in 9. Mutations were detected in four of the nine sporadic cases. Overall, five nonsense mutations, four missense mutations, two deletions, one insertion, and one donor splice mutation were identified. All but two of the 64 genetically defined patients reported episodes of Ataxia (two members of one family only had progressive Ataxia). All but one had onset before age 20 and all but four had interictal nystagmus. Migraine headaches occurred in more than half, and about two thirds reported a good response to treatment with acetazolamide. Vertigo and weakness accompanied the Ataxia in more than half of the genetically defined patients. One family had multiple members with epilepsy. A wide range of mutations in CACNA1A were associated with Episodic Ataxia. Four of 13 were missense mutations; the remainder predicted truncated proteins. The mutations were scattered throughout the gene, and only 2 of the 13 mutations identified in our laboratory have been reported by other laboratories, so it will not be possible to screen a few “hot spots” in CACNA1A . Overall, the type of mutation, missense versus nonsense, or the location of altered or truncated amino acid residues did not predict the clinical phenotype.
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Spinocerebellar Ataxia type 6 with positional vertigo and acetazolamide responsive Episodic Ataxia
Journal of neurology neurosurgery and psychiatry, 1998Co-Authors: Joanna C. Jen, Stanley F Nelson, Qing Yue, Juliana Karrim, Robert W BalohAbstract:The SCA6 mutation, a small expansion of a CAG repeat in a calcium channel gene CACNA1A, was identified in three pedigrees. Point mutations in other parts of the gene CACNA1A were excluded and new clinical features of SCA6 reported—namely, central positional nystagmus and Episodic Ataxia responsive to acetazolamide. The three allelic disorders, Episodic Ataxia type 2, familial hemiplegic migraine, and SCA6, have overlapping clinical features.
Paola Imbrici - One of the best experts on this subject based on the ideXlab platform.
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Identification of a New de Novo Mutation Underlying Regressive Episodic Ataxia Type I
Frontiers Media S.A., 2018Co-Authors: Zeynep S. Karalok, Paola Imbrici, M. Pessia, Alfredo Megaro, Marta Cenciarini, Alev Guven, Sonia M. Hasan, Birce D. Taskin, Serdar CeylanerAbstract:Episodic Ataxia type 1 (EA1), a Shaker-like K+channelopathy, is a consequence of genetic anomalies in the KCNA1 gene that lead to dysfunctions in the voltage-gated K+ channel Kv1. 1. Generally, KCNA1 mutations are inherited in an autosomal dominant manner. Here we report the clinical phenotype of an EA1 patient characterized by Ataxia attacks that decrease in frequency with age, and eventually leading to therapy discontinuation. A new de novo mutation (c.932G>A) that changed a highly conserved glycine residue into an aspartate (p.G311D) was identified by using targeted next-generation sequencing. The conserved glycine is located in the S4–S5 linker, a crucial domain controlling Kv1.1 channel gating. In silico analyses predicted the mutation deleterious. Heterologous expression of the mutant (Kv1.1-G311D) channels resulted in remarkably decreased amplitudes of measured current, confirming the identified variant is pathogenic. Collectively, these findings corroborate the notion that EA1 also results from de novo variants and point out that regardless of the mutation-induced deleterious loss of Kv1.1 channel function the Ataxia phenotype may improve spontaneously
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Data_Sheet_1_Identification of a New de Novo Mutation Underlying Regressive Episodic Ataxia Type I.DOCX
2018Co-Authors: Zeynep S. Karalok, Paola Imbrici, M. Pessia, Alfredo Megaro, Marta Cenciarini, Alev Guven, Sonia M. Hasan, Birce D. Taskin, Serdar Ceylaner, Maria C. D'adamoAbstract:Episodic Ataxia type 1 (EA1), a Shaker-like K+channelopathy, is a consequence of genetic anomalies in the KCNA1 gene that lead to dysfunctions in the voltage-gated K+ channel Kv1. 1. Generally, KCNA1 mutations are inherited in an autosomal dominant manner. Here we report the clinical phenotype of an EA1 patient characterized by Ataxia attacks that decrease in frequency with age, and eventually leading to therapy discontinuation. A new de novo mutation (c.932G>A) that changed a highly conserved glycine residue into an aspartate (p.G311D) was identified by using targeted next-generation sequencing. The conserved glycine is located in the S4–S5 linker, a crucial domain controlling Kv1.1 channel gating. In silico analyses predicted the mutation deleterious. Heterologous expression of the mutant (Kv1.1-G311D) channels resulted in remarkably decreased amplitudes of measured current, confirming the identified variant is pathogenic. Collectively, these findings corroborate the notion that EA1 also results from de novo variants and point out that regardless of the mutation-induced deleterious loss of Kv1.1 channel function the Ataxia phenotype may improve spontaneously.
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a novel kcna1 mutation identified in an italian family affected by Episodic Ataxia type 1
Neuroscience, 2008Co-Authors: Paola Imbrici, Francesca Gualandi, Maria Cristina Dadamo, Taddei M Masieri, P Cudia, D De Grandis, R Mannucci, Ildo Nicoletti, Stephen J Tucker, Alessandra FerliniAbstract:Abstract Episodic Ataxia type 1 (EA1) is a rare human neurological syndrome characterized by continuous myokymia and attacks of generalized Ataxia that can be triggered by abrupt movements, emotional stress and fatigue. An Italian family has been identified where related members displayed continuous myokymia, episodes of Ataxia, attacks characterized by myokymia only, and neuromyotonia. A novel missense mutation (F414C), in the C-terminal region of the K + channel Kv1.1, was identified in the affected individuals. The mutant homotetrameric channels were non-functional in Xenopus laevis oocytes. In addition, heteromeric channels resulting from the co-expression of wild-type Kv1.1 and Kv1.1(F414C), or wild-type Kv1.2 and Kv1.1(F414C) subunits displayed reduced current amplitudes and altered gating properties. This indicates that the pathogenic effect of this KCNA1 mutation is likely to be related to the defective functional properties we have identified.
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premature stop codons in a facilitating ef hand splice variant of cav2 1 cause Episodic Ataxia type 2
Neurobiology of Disease, 2008Co-Authors: Tracey D. Graves, L H Eunson, Paola Imbrici, E E Kors, Gisela M Terwindt, J Haan, R R Frants, Michel D Ferrari, Peter J Goadsby, M.G. HannaAbstract:Abstract Premature stop codons in CACNA1A , which encodes the α 1A subunit of neuronal P/Q-type (Ca V 2.1) Ca 2+ channels, cause Episodic Ataxia type 2 (EA2). CACNA1A undergoes extensive alternative splicing, which contributes to the pharmacological and kinetic heterogeneity of Ca V 2.1-mediated Ca 2+ currents. We identified three novel heterozygous stop codon mutations associated with EA2 in an alternately spliced exon (37A), which encodes part of an EF-hand motif required for Ca 2+ -dependent facilitation. One family had a C to G transversion (Y1854X). A dinucleotide deletion results in the same premature stop codon in a second family, and a further single nucleotide change leads to a different truncation (R1858X) in a de novo case of EA2. Expression studies of the Y1854X mutation revealed loss of Ca V 2.1-mediated current. Because these mutations do not affect the alternate exon 37B, these findings reveal unexpected dependence of cerebellar function on intact exon 37A-containing Ca V 2.1 channels.
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Mutations in the KCNA1 gene associated with Episodic Ataxia type-1 syndrome impair heteromeric voltage-gated K+ channel function
1999Co-Authors: Maria Cristina Dadamo, Paola Imbrici, F. Sponcichetti, M. PessiaAbstract: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 ~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
Ronald B. Emeson - One of the best experts on this subject based on the ideXlab platform.
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Mutations underlying Episodic Ataxia type-1 antagonize Kv1.1 RNA editing.
Scientific Reports, 2017Co-Authors: Elizabeth A. Ferrick-kiddie, Joshua J. C. Rosenthal, Gregory D. Ayers, Ronald B. EmesonAbstract:: Adenosine-to-inosine RNA editing in transcripts encoding the voltage-gated potassium channel Kv1.1 converts an isoleucine to valine codon for amino acid 400, speeding channel recovery from inactivation. Numerous Kv1.1 mutations have been associated with the human disorder Episodic Ataxia Type-1 (EA1), characterized by stress-induced Ataxia, myokymia, and increased prevalence of seizures. Three EA1 mutations, V404I, I407M, and V408A, are located within the RNA duplex structure required for RNA editing. Each mutation decreased RNA editing both in vitro and using an in vivo mouse model bearing the V408A allele. Editing of transcripts encoding mutant channels affects numerous biophysical properties including channel opening, closing, and inactivation. Thus EA1 symptoms could be influenced not only by the direct effects of the mutations on channel properties, but also by their influence on RNA editing. These studies provide the first evidence that mutations associated with human genetic disorders can affect cis-regulatory elements to alter RNA editing.