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Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene

Episodic ataxia type 1 (EA1) is an autosomal dominant K(+) channelopathy which manifests with short attacks of cerebellar ataxia and dysarthria, and may also show interictal myokymia. Episodes can be triggered by emotional or physical stress, startle response, sudden postural change or fever. Here w...

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Autores principales: D'Adamo, Maria C., Gallenmüller, Constanze, Servettini, Ilenio, Hartl, Elisabeth, Tucker, Stephen J., Arning, Larissa, Biskup, Saskia, Grottesi, Alessandro, Guglielmi, Luca, Imbrici, Paola, Bernasconi, Pia, Di Giovanni, Giuseppe, Franciolini, Fabio, Catacuzzeno, Luigi, Pessia, Mauro, Klopstock, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295438/
https://www.ncbi.nlm.nih.gov/pubmed/25642194
http://dx.doi.org/10.3389/fphys.2014.00525
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author D'Adamo, Maria C.
Gallenmüller, Constanze
Servettini, Ilenio
Hartl, Elisabeth
Tucker, Stephen J.
Arning, Larissa
Biskup, Saskia
Grottesi, Alessandro
Guglielmi, Luca
Imbrici, Paola
Bernasconi, Pia
Di Giovanni, Giuseppe
Franciolini, Fabio
Catacuzzeno, Luigi
Pessia, Mauro
Klopstock, Thomas
author_facet D'Adamo, Maria C.
Gallenmüller, Constanze
Servettini, Ilenio
Hartl, Elisabeth
Tucker, Stephen J.
Arning, Larissa
Biskup, Saskia
Grottesi, Alessandro
Guglielmi, Luca
Imbrici, Paola
Bernasconi, Pia
Di Giovanni, Giuseppe
Franciolini, Fabio
Catacuzzeno, Luigi
Pessia, Mauro
Klopstock, Thomas
author_sort D'Adamo, Maria C.
collection PubMed
description Episodic ataxia type 1 (EA1) is an autosomal dominant K(+) channelopathy which manifests with short attacks of cerebellar ataxia and dysarthria, and may also show interictal myokymia. Episodes can be triggered by emotional or physical stress, startle response, sudden postural change or fever. Here we describe a 31-year-old man displaying markedly atypical symptoms, including long-lasting attacks of jerking muscle contractions associated with hyperthermia, severe migraine, and a relatively short-sleep phenotype. A single nucleotide change in KCNA1 (c.555C>G) was identified that changes a highly conserved residue (p.C185W) in the first transmembrane segment of the voltage-gated K(+) channel Kv1.1. The patient is heterozygous and the mutation was inherited from his asymptomatic mother. Next generation sequencing revealed no variations in the CACNA1A, CACNB4, KCNC3, KCNJ10, PRRT2 or SCN8A genes of either the patient or mother, except for a benign variant in SLC1A3. Functional analysis of the p.C185W mutation in KCNA1 demonstrated a deleterious dominant-negative phenotype where the remaining current displayed slower activation kinetics, subtle changes in voltage-dependence and faster recovery from slow inactivation. Structural modeling also predicts the C185W mutation to be functionally deleterious. This description of novel clinical features, associated with a Kv1.1 mutation highlights a possibly unrecognized relationship between K(+) channel dysfunction, hyperthermia and migraine in EA1, and suggests that thorough assessments for these symptoms should be carefully considered for all patients affected by EA1.
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spelling pubmed-42954382015-01-30 Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene D'Adamo, Maria C. Gallenmüller, Constanze Servettini, Ilenio Hartl, Elisabeth Tucker, Stephen J. Arning, Larissa Biskup, Saskia Grottesi, Alessandro Guglielmi, Luca Imbrici, Paola Bernasconi, Pia Di Giovanni, Giuseppe Franciolini, Fabio Catacuzzeno, Luigi Pessia, Mauro Klopstock, Thomas Front Physiol Physiology Episodic ataxia type 1 (EA1) is an autosomal dominant K(+) channelopathy which manifests with short attacks of cerebellar ataxia and dysarthria, and may also show interictal myokymia. Episodes can be triggered by emotional or physical stress, startle response, sudden postural change or fever. Here we describe a 31-year-old man displaying markedly atypical symptoms, including long-lasting attacks of jerking muscle contractions associated with hyperthermia, severe migraine, and a relatively short-sleep phenotype. A single nucleotide change in KCNA1 (c.555C>G) was identified that changes a highly conserved residue (p.C185W) in the first transmembrane segment of the voltage-gated K(+) channel Kv1.1. The patient is heterozygous and the mutation was inherited from his asymptomatic mother. Next generation sequencing revealed no variations in the CACNA1A, CACNB4, KCNC3, KCNJ10, PRRT2 or SCN8A genes of either the patient or mother, except for a benign variant in SLC1A3. Functional analysis of the p.C185W mutation in KCNA1 demonstrated a deleterious dominant-negative phenotype where the remaining current displayed slower activation kinetics, subtle changes in voltage-dependence and faster recovery from slow inactivation. Structural modeling also predicts the C185W mutation to be functionally deleterious. This description of novel clinical features, associated with a Kv1.1 mutation highlights a possibly unrecognized relationship between K(+) channel dysfunction, hyperthermia and migraine in EA1, and suggests that thorough assessments for these symptoms should be carefully considered for all patients affected by EA1. Frontiers Media S.A. 2015-01-15 /pmc/articles/PMC4295438/ /pubmed/25642194 http://dx.doi.org/10.3389/fphys.2014.00525 Text en Copyright © 2015 D'Adamo, Gallenmüller, Servettini, Hartl, Tucker, Arning, Biskup, Grottesi, Guglielmi, Imbrici, Bernasconi, Di Giovanni, Franciolini, Catacuzzeno, Pessia and Klopstock. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Physiology
D'Adamo, Maria C.
Gallenmüller, Constanze
Servettini, Ilenio
Hartl, Elisabeth
Tucker, Stephen J.
Arning, Larissa
Biskup, Saskia
Grottesi, Alessandro
Guglielmi, Luca
Imbrici, Paola
Bernasconi, Pia
Di Giovanni, Giuseppe
Franciolini, Fabio
Catacuzzeno, Luigi
Pessia, Mauro
Klopstock, Thomas
Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene
title Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene
title_full Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene
title_fullStr Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene
title_full_unstemmed Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene
title_short Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene
title_sort novel phenotype associated with a mutation in the kcna1(kv1.1) gene
topic Physiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295438/
https://www.ncbi.nlm.nih.gov/pubmed/25642194
http://dx.doi.org/10.3389/fphys.2014.00525
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