RESUMO
Timothy syndrome (OMIM #601005) is a rare disease caused by variants in the gene CACNA1C . Timothy syndrome patients were first identified as having a cardiac presentation of Long QT and syndactyly of the fingers and/or toes, and an identical variant in CACNA1C , Gly406Arg. However, since this original identification, more individuals harboring diverse variants in CACNA1C have been identified and have presented with various cardiac and extra-cardiac symptoms. Furthermore, it has remained underexplored whether individuals harboring canonical Gly406Arg variants in mutually exclusive exon 8A (Timothy syndrome 1) or exon 8 (Timothy syndrome 2) have additional symptoms. Here, we describe the first Natural History Study for Timothy syndrome, providing a thorough resource describing the current understanding of disease manifestation in Timothy syndrome patients. Parents of Timothy syndrome children were queried regarding a wide-ranging set of symptoms and features via a survey. Importantly, we find that in addition to cardiac concerns, Timothy syndrome patients commonly share extra-cardiac features including neurodevelopmental impairments, hypoglycemia, and respiratory problems. Our work expands the current understanding of the disorder to better inform the care of Timothy syndrome patients.
RESUMO
BACKGROUND: CACNA1C encodes the voltage-gated L-type calcium channel CaV1.2. A specific gain-of-function pathogenic variant in CACNA1C causes Timothy syndrome type 1 (TS1) with cardiac long QT syndrome, syndactyly, and neuropsychiatric symptoms. Our previous work found that the TS1 mutation alters neuronal activity-dependent signaling and interneuron migration. Recent case series highlighted a broader spectrum of CACNA1C-related disorder (CRD) that includes isolated cardiac disease, isolated neurologic deficits, and TS, but it is unknown how the clinical presentation of other CRD variants relates to neural defects. We surveyed individuals with CRD to define the neuropsychiatric and developmental phenotype in an effort to guide future research into the role of calcium channels in neural development. METHODS: Caregivers of and individuals with CRD completed an online survey of pre- and perinatal events, cardiac events, developmental milestones, neuropsychiatric symptoms, and neuropsychiatric diagnoses. Multiple Mann-Whitney tests were used for comparison of categorical values and Fisher exact test for comparison of categorical variables between participants with and without cardiac arrhythmia. RESULTS: Twenty-four participants with germline CACNA1C variants including TS1 completed the survey. The most common neuropsychiatric symptoms and/or diagnoses were developmental delay in 92%, incoordination in 71%, hypotonia in 67%, autism spectrum disorder in 50% (autistic features in 92%), seizures in 37.5%, and attention-deficit/hyperactivity disorder in 21% of participants. There were no significant differences in symptoms between participants with and without arrhythmia. CONCLUSIONS: In our CRD cohort, there was an increased prevalence of multiple neuropsychiatric symptoms compared with the general population. These findings indicate the key role of CaV1.2 in brain development and the clinical importance of screening and therapeutically addressing neuropsychiatric symptoms in all individuals with CRD. Future directions include deep phenotyping of neuropsychiatric symptoms and efforts to relate these symptoms to cellular defects.
Assuntos
Transtorno do Espectro Autista , Síndrome do QT Longo , Gravidez , Feminino , Humanos , Estudos Transversais , Transtorno do Espectro Autista/genética , Síndrome do QT Longo/genética , Síndrome do QT Longo/diagnóstico , Mutação , Fenótipo , Canais de Cálcio Tipo L/genéticaRESUMO
Timothy Syndrome (TS) (OMIM #601005) is a rare autosomal dominant syndrome caused by variants in CACNA1C, which encodes the α1C subunit of the voltage-gated calcium channel Cav1.2. TS is classically caused by only a few different genetic changes and characterized by prolonged QT interval, syndactyly, and neurodevelopmental delay; however, the number of identified TS-causing variants is growing, and the resulting symptom profiles are incredibly complex and variable. Here, we aim to review the genetic and clinical findings of all published case reports of TS to date. We discuss multiple possible mechanisms for the variability seen in clinical features across these cases, including mosaicism, genetic background, isoform complexity of CACNA1C and differential expression of transcripts, and biophysical changes in mutant CACNA1C channels. Finally, we propose future research directions such as variant validation, in vivo modeling, and natural history characterization.
RESUMO
Aims: Timothy syndrome (TS) is an extremely rare multisystem disorder characterized by marked QT prolongation, syndactyly, seizures, behavioural abnormalities, immunodeficiency, and hypoglycaemia. The aim of this study was to categorize the phenotypes and examine the outcomes of patients with TS. Methods and results: All patients diagnosed with TS in the United Kingdom over a 24-year period were reviewed. Fifteen centres in the British Congenital Arrhythmia Group network were contacted to partake in the study. Six patients with TS were identified over a 24-year period (4 boys and 2 girls). Five out of the six patients were confirmed to have a CACNA1C mutation (p.Gly406Arg) and the other patient was diagnosed clinically. Early presentation with heart block, due to QT prolongation was frequently seen. Four are still alive, two of these have a pacemaker and two have undergone defibrillator implantation. Five out of six patients have had a documented cardiac arrest with three occurring under general anaesthesia. Two patients suffered a cardiac arrest while in hospital and resuscitation was unsuccessful, despite immediate access to a defibrillator. Surviving patients seem to have mild developmental delay and learning difficulties. Conclusion: Timothy syndrome is a rare disorder with a high attrition rate if undiagnosed. Perioperative cardiac arrests are common and not always amenable to resuscitation. Longer-term survival is possible, however, patients invariably require pacemaker or defibrillator implantation.
Assuntos
Transtorno Autístico , Síndrome do QT Longo , Sindactilia , Transtorno Autístico/complicações , Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Transtorno Autístico/terapia , Canais de Cálcio Tipo L/genética , Estimulação Cardíaca Artificial , Desfibriladores Implantáveis , Cardioversão Elétrica/instrumentação , Eletrocardiografia , Feminino , Predisposição Genética para Doença , Parada Cardíaca/etiologia , Parada Cardíaca/fisiopatologia , Parada Cardíaca/terapia , Bloqueio Cardíaco/etiologia , Bloqueio Cardíaco/fisiopatologia , Bloqueio Cardíaco/terapia , Humanos , Lactente , Recém-Nascido , Síndrome do QT Longo/complicações , Síndrome do QT Longo/genética , Síndrome do QT Longo/fisiopatologia , Síndrome do QT Longo/terapia , Masculino , Mutação , Marca-Passo Artificial , Fenótipo , Prognóstico , Ressuscitação , Sindactilia/complicações , Sindactilia/genética , Sindactilia/fisiopatologia , Sindactilia/terapia , Fatores de Tempo , Reino UnidoRESUMO
BACKGROUND: Timothy syndrome (TS) is a rare long-QT syndrome caused by CACNA1C mutations G406R in exon 8A (TS1) and G402S/G406R in exon 8 (TS2). Management of TS is a challenge and prognosis is poor. This study aimed to explore the inheritance pattern and mechanism of an INa blocker, mexiletine, to improve clinical manifestations in TS. METHODS AND RESULTS: A 2-year-old Chinese girl with a typical TS1 phenotype underwent candidate gene screening. Qualitative and quantitative cloning sequence and analyses for mosaicism were performed on family members. Therapeutic effects of mexiletine were evaluated using ECG and Holter monitoring. The electrophysiological effect of mexiletine was evaluated in a TS model using rabbit ventricular wedges. The proband with severe syndactyly and delayed language skills was identified harboring a G406R mutation in CACNA1C. Her baseline ECG showed markedly prolonged QTc, 2:1 AV block and macro-T wave alternans. G406R was absent in her mother but expressed in her father's oral mucosa, sperm, and white blood cells, indicating a mosaic carrier. Although asymptomatic, he exhibited mild QTc prolongation (470-490 ms) and syndactyly. Mexiletine shortened QTc from 584 to 515 ms, blunted QT-RR relationship, and abolished 2:1 AV block and T wave alternans in the girl. In in vitro studies, mexiletine inhibited late INa with IC50 of 17.6±1.9 µmol/L and attenuated brady-dependent QT prolongation and reduced QT-RR slope in the TS model using BayK 8644. CONCLUSIONS: Mexiletine shortened QTc, attenuated QT-RR slope, abolished 2:1 AV block and T wave alternans in a TS1 patient and TS model via inhibition of late INa.
Assuntos
Síndrome do QT Longo/tratamento farmacológico , Síndrome do QT Longo/genética , Mexiletina/uso terapêutico , Canais de Sódio/efeitos dos fármacos , Sindactilia/tratamento farmacológico , Sindactilia/genética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico , Animais , Transtorno Autístico , Pré-Escolar , Análise Mutacional de DNA , Ecocardiografia Doppler/métodos , Eletrocardiografia/métodos , Eletrocardiografia Ambulatorial/métodos , Feminino , Seguimentos , Regulação da Expressão Gênica no Desenvolvimento , Estudos de Associação Genética , Testes Genéticos , Humanos , Síndrome do QT Longo/diagnóstico , Modelos Animais , Células Musculares/efeitos dos fármacos , Coelhos , Índice de Gravidade de Doença , Sindactilia/diagnóstico , Resultado do TratamentoRESUMO
Timothy syndrome type 1 (TS-1) is a rare disorder that affects multiple organ systems and has a high incidence of sudden death due to profound QT prolongation and resultant ventricular arrhythmias. All previously described cases of TS-1 are the result of a missense mutation in exon 8A (p.G406R), an alternatively spliced variant of the L-type calcium channel gene (Ca(v)1.2, CACNA1C). Most patients reported in the literature represent highly affected individuals who present early in life with severe cardiac and neurological manifestations. Here, we describe somatic mosaicism in TS-1 patients with less severe manifestations than the typical TS-1 patient. These findings suggest that the TS prognosis may not be as dismal as previously reported. Moreover, our findings have implications for genetic counseling in that previously described de novo TS mutations may represent cases of parental mosaicism and warrant careful genotyping of parental tissue other than peripheral blood lymphocytes.
Assuntos
Síndrome do QT Longo/genética , Síndrome do QT Longo/patologia , Mosaicismo , Fenótipo , Sindactilia/genética , Sindactilia/patologia , Adolescente , Transtorno Autístico , Sequência de Bases , Canais de Cálcio Tipo L/genética , Eletrocardiografia , Éxons/genética , Feminino , Genótipo , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Dados de Sequência Molecular , Análise de Sequência de DNARESUMO
OBJECTIVE: Andersen syndrome (AS) is a rare genetic disease caused by mutations of the potassium channel Kir2.1 (KCNJ2). We identified two unrelated patients with mutations in the slide helix of Kir2.1 leading to AS. The functional consequences of these two mutations, Y68D and D78Y, were studied and compared with previously reported slide helix mutations. METHODS: Channel function and surface expression were studied by voltage clamp recordings and a chemiluminescence assay in Xenopus laevis oocytes and by patch clamp recordings and fluorescence microscopy in HEK293 cells. In addition, a phosphatidylinositol bisphosphate (PIP(2)) binding assay and a yeast-two-hybrid assay were used to characterize the molecular mechanisms by which slide helix mutations cause AS. RESULTS: Neither mutant channel produced any current, but both had dominant negative effects on Kir2.2, Kir2.3, and Kir2.4 channels. We show that Y68D, D78Y, and previously reported AS mutations are clustered on the hydrophilic, cytosolic side of the slide helix and traffic normally to the plasma membrane. The in vitro lipid binding assay indicated that Y68D or D78Y N-terminal peptides bind PIP(2) similar to wild-type peptides. Yeast-two-hybrid assays showed that AS-associated mutations disturb the interaction between the slide helix and the C-terminal domain of the channel protein. CONCLUSION: Our experiments indicate a new disease-causing mechanism independent of trafficking and PIP(2) binding defects. Our findings suggest that the hydrophilic side of the slide helix interacts with a specific domain of the C-terminus facing the membrane. This interaction, which may be required for normal gating both in homomeric and heteromeric Kir2 channels, is disturbed by several mutations causing AS.
Assuntos
Síndrome de Andersen/genética , Ativação do Canal Iônico/genética , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Adulto , Síndrome de Andersen/metabolismo , Animais , Células COS , Linhagem Celular , Chlorocebus aethiops , Análise Mutacional de DNA , Feminino , Expressão Gênica , Humanos , Microscopia de Fluorescência , Oócitos/metabolismo , Técnicas de Patch-Clamp , Fenótipo , Canais de Potássio Corretores do Fluxo de Internalização/análise , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Técnicas do Sistema de Duplo-Híbrido , XenopusRESUMO
BACKGROUND: Timothy syndrome is a multisystem disorder associated with QT interval prolongation and ventricular cardiac arrhythmias. The syndrome has been linked to mutations in Ca(V)1.2 resulting in gain of function of the L-type calcium current (I(Ca,L)). Ranolazine is an antianginal agent shown to exert an antiarrhythmic effect in experimental models of long QT syndrome. OBJECTIVE: The purpose of this study was to develop and characterize an experimental model of Timothy syndrome by using BayK8644 to mimic the gain of function of I(Ca,L) and to examine the effects of ranolazine. METHODS: Action potentials from epicardial and M regions and a pseudo-electrocardiogram (ECG) were simultaneously recorded from coronary-perfused left ventricular wedge preparations, before and after addition of BayK8644 (1 microM). RESULTS: BayK8644 preferentially prolonged action potential duration of the M cell, leading to prolongation of the QT interval and an increase in transmural dispersion of repolarization (from 44.3 +/- 7 ms to 86.5 +/- 25 ms). Stimulation at cycle lengths of 250-500 ms led to ST-T wave alternans due to alternation of the plateau voltage of the M cell action potential as well as development of delayed afterdepolarizations in epicardial and M cell action potentials. Ventricular extrasystoles and tachycardia (monomorphic, bidirectional, or torsades de pointes) developed spontaneously or after rapid pacing. Peak and late I(Na) were unaffected by BayK8644. Clinically relevant concentrations of ranolazine (10 microM) suppressed all actions of BayK8644. CONCLUSION: A left ventricular wedge model of long QT syndrome created by augmentation of I(Ca,L) recapitulates the ECG and arrhythmic manifestations of Timothy syndrome, which can be suppressed by ranolazine.
Assuntos
Acetanilidas/farmacologia , Antiarrítmicos/farmacologia , Eletrocardiografia , Síndrome do QT Longo/tratamento farmacológico , Síndrome do QT Longo/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Piperazinas/farmacologia , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/efeitos adversos , Potenciais de Ação/efeitos dos fármacos , Análise de Variância , Animais , Agonistas dos Canais de Cálcio/efeitos adversos , Modelos Animais de Doenças , Cães , Endocárdio/citologia , Endocárdio/efeitos dos fármacos , Endocárdio/fisiopatologia , Inibidores Enzimáticos/farmacologia , Ventrículos do Coração/citologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Síndrome do QT Longo/etiologia , Técnicas de Patch-Clamp , Pericárdio/citologia , Pericárdio/efeitos dos fármacos , Pericárdio/fisiopatologia , Ranolazina , Taquicardia Ventricular/induzido quimicamente , Taquicardia Ventricular/tratamento farmacológico , Taquicardia Ventricular/fisiopatologia , Torsades de Pointes/induzido quimicamente , Torsades de Pointes/tratamento farmacológico , Torsades de Pointes/fisiopatologia , Complexos Ventriculares Prematuros/induzido quimicamente , Complexos Ventriculares Prematuros/tratamento farmacológico , Complexos Ventriculares Prematuros/fisiopatologiaRESUMO
Timothy syndrome (TS) is a multisystem disorder that causes syncope and sudden death from cardiac arrhythmias. Prominent features include congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. All TS individuals have syndactyly (webbing of fingers and toes). We discovered that TS resulted from a recurrent, de novo cardiac L-type calcium channel (CaV1.2) mutation, G406R. G406 is located in alternatively spliced exon 8A, encoding transmembrane segment S6 of domain I. Here, we describe two individuals with a severe variant of TS (TS2). Neither child had syndactyly. Both individuals had extreme prolongation of the QT interval on electrocardiogram, with a QT interval corrected for heart rate ranging from 620 to 730 ms, causing multiple arrhythmias and sudden death. One individual had severe mental retardation and nemaline rod skeletal myopathy. We identified de novo missense mutations in exon 8 of CaV1.2 in both individuals. One was an analogous mutation to that found in exon 8A in classic TS, G406R. The other mutation was G402S. Exon 8 encodes the same region as exon 8A, and the two are mutually exclusive. The spliced form of CaV1.2 containing exon 8 is highly expressed in heart and brain, accounting for approximately 80% of CaV1.2 mRNAs. G406R and G402S cause reduced channel inactivation, resulting in maintained depolarizing L-type calcium currents. Computer modeling showed prolongation of cardiomyocyte action potentials and delayed afterdepolarizations, factors that increase risk of arrhythmia. These data indicate that gain-of-function mutations of CaV1.2 exons 8 and 8A cause distinct forms of TS.
Assuntos
Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Mutação de Sentido Incorreto/genética , Potenciais de Ação/fisiologia , Sequência de Aminoácidos , Animais , Arritmias Cardíacas/complicações , Encéfalo/metabolismo , Canais de Cálcio Tipo L/química , Pré-Escolar , Eletrofisiologia , Éxons/genética , Feminino , Glicina/genética , Glicina/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Miocárdio/metabolismo , Miocárdio/patologia , Oócitos/metabolismo , Linhagem , Fenótipo , Síndrome , XenopusRESUMO
Ca(V)1.2, the cardiac L-type calcium channel, is important for excitation and contraction of the heart. Its role in other tissues is unclear. Here we present Timothy syndrome, a novel disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. In every case, Timothy syndrome results from the identical, de novo Ca(V)1.2 missense mutation G406R. Ca(V)1.2 is expressed in all affected tissues. Functional expression reveals that G406R produces maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation. This likely induces intracellular Ca(2+) overload in multiple cell types. In the heart, prolonged Ca(2+) current delays cardiomyocyte repolarization and increases risk of arrhythmia, the ultimate cause of death in this disorder. These discoveries establish the importance of Ca(V)1.2 in human physiology and development and implicate Ca(2+) signaling in autism.
Assuntos
Arritmias Cardíacas/fisiopatologia , Transtorno Autístico/fisiopatologia , Canais de Cálcio Tipo L/genética , Sinalização do Cálcio/genética , Doenças Genéticas Inatas/fisiopatologia , Mutação de Sentido Incorreto/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Potenciais de Ação/genética , Animais , Arritmias Cardíacas/complicações , Arritmias Cardíacas/genética , Transtorno Autístico/complicações , Transtorno Autístico/genética , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Química Encefálica/genética , Células CHO , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Membrana Celular/genética , Membrana Celular/metabolismo , Criança , Cricetinae , Feminino , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/genética , Coração/fisiopatologia , Humanos , Recém-Nascido , Deformidades Congênitas dos Membros/complicações , Deformidades Congênitas dos Membros/genética , Masculino , Camundongos , Miócitos Cardíacos/metabolismo , Neurônios/metabolismo , Oócitos , Linhagem , Síndrome , Xenopus laevisRESUMO
OBJECTIVES: The purpose of this research was to determine whether an intronic variant (T1945+6C) in KCNH2 is a disease-causing mutation, and if expanded phenotyping criteria produce improved identification of long QT syndrome (LQTS) patients. BACKGROUND: Long QT syndrome is usually caused by mutations in conserved coding regions or invariant splice sites, yet no mutation is found in 30% to 50% of families. In one such family, we identified an intronic variant in KCNH2. Long QT syndrome diagnosis is hindered by reduced penetrance, as the long QT phenotype is absent on baseline electrocardiogram (ECG) in about 30%. METHODS: Fifty-two family members were phenotyped by baseline QTc, QTc maximum on serial ECGs (Ser QTc-max), and on exercise ECGs (Ex QTc-max) and by T-wave patterns. Linkage analysis tested association of the intronic change with phenotype. The consequences of T1945+6C on splicing was studied using a minigene system and on function by heterologous expression. RESULTS: Expanded phenotype/pedigree criteria identified 23 affected and 29 unaffected. Affected versus unaffected had baseline QTc 484 +/- 48 ms versus 422 +/- 20 ms, Ser QTc-max 508 +/- 48 ms versus 448 +/- 10 ms, Ex QTc-max 513 +/- 54 ms versus 444 +/- 11 ms, and LQT2 T waves in 87% versus 0%. Linkage analysis demonstrated a logarithm of odds score of 10.22. Splicing assay showed T1945+6C caused downstream intron retention. Complementary deoxyribonucleic acid with retained intron 7 failed to produce functional channels. CONCLUSIONS: T1945+6C is a disease-causing mutation. It alters KCNH2 splicing and cosegregates with the LQT2 phenotype. Expanded ECG criteria plus pedigree analysis provided accurate clinical diagnosis of all carriers including those with reduced penetrance. Intronic mutations may be responsible for LQTS in some families with otherwise negative mutation screening.
Assuntos
Íntrons/genética , Síndrome do QT Longo/genética , Mutação/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Canal de Potássio ERG1 , Eletrocardiografia , Canais de Potássio Éter-A-Go-Go , Saúde da Família , Seguimentos , Triagem de Portadores Genéticos , Ligação Genética/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Canais de Potássio/genética , RNA Complementar/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatística como AssuntoRESUMO
BACKGROUND: Long QT syndrome (LQTS) predisposes affected individuals to sudden death from cardiac arrhythmias. Although most LQTS individuals do not have cardiac events, significant phenotypic variability exists within families. Probands can be very symptomatic. The mechanism of this phenotypic variability is not understood. METHODS AND RESULTS: Genetic analyses of KVLQT1, HERG, KCNE1, KCNE2, and SCN5A detected compound mutations in 20 of 252 LQTS probands (7.9%). Carriers of 2 mutations had longer QTc intervals (527+/-54 versus 489+/-44 ms; P<0.001); all had experienced cardiac events (20 of 20 [100%] versus 128 of 178 [72%]; P<0.01) and were 3.5-fold more likely to have cardiac arrest (9 of 16 [56%] versus 45 of 167 [27%]; P<0.01; OR, 3.5; 95% CI, 1.2 to 9.9) compared with probands with 1 or no identified mutation. Two-microelectrode voltage clamp of Xenopus oocytes was used to characterize the properties of variant slow delayed rectifier potassium (I(Ks)) channels identified in 7 of the probands. When wild-type and variant subunits were coexpressed in appropriate ratios to mimic the genotype of the proband, the reduction in I(Ks) density was equivalent to the additive effects of the single mutations. CONCLUSIONS: LQTS-associated compound mutations cause a severe phenotype and are more common than expected. Individuals with compound mutations need to be identified, and their management should be tailored to their increased risk for arrhythmias.
Assuntos
Canais Iônicos/genética , Síndrome do QT Longo/genética , Mutação , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Animais , Células Cultivadas , Canal de Potássio ERG1 , Condutividade Elétrica , Canais de Potássio Éter-A-Go-Go , Feminino , Humanos , Canais de Potássio KCNQ , Canal de Potássio KCNQ1 , Síndrome do QT Longo/diagnóstico , Masculino , Mutagênese Sítio-Dirigida , Canal de Sódio Disparado por Voltagem NAV1.5 , Técnicas de Patch-Clamp , Linhagem , Canais de Potássio/genética , Canais de Potássio/fisiologia , Canais de Sódio/genética , Xenopus laevisRESUMO
OBJECTIVES: The purpose of this study was to determine the prevalence and spectrum of nonsynonymous polymorphisms (amino acid variants) in the cardiac sodium channel among healthy subjects. BACKGROUND: Pathogenic mutations in the cardiac sodium channel gene, SCN5A, cause approximately 15 to 20% of Brugada syndrome (BrS1), 5 to 10% of long QT syndrome (LQT3), and 2 to 5% of sudden infant death syndrome. METHODS: Using single-stranded conformation polymorphism, denaturing high-performance liquid chromatography, and/or direct DNA sequencing, mutational analysis of the protein-encoding exons of SCN5A was performed on 829 unrelated, anonymous healthy subjects: 319 black, 295 white, 112 Asian, and 103 Hispanic. RESULTS: In addition to the four known common polymorphisms (R34C, H558R, S1103Y, and R1193Q), four relatively ethnic-specific polymorphisms were identified: R481W, S524Y, P1090L, and V1951L. Overall, 39 distinct missense variants (28 novel) were elucidated. Nineteen variants (49%) were found only in the black cohort. Only seven variants (18%) localized to transmembrane-spanning domains. Four variants (F1293S, R1512W, and V1951L cited previously as BrS1-causing mutations and S1787N previously published as a possible LQT3-causing mutation) were identified in this healthy cohort. CONCLUSIONS: This study provides the first comprehensive determination of the prevalence and spectrum of cardiac sodium channel variants in healthy subjects from four distinct ethnic groups. This compendium of SCN5A variants is critical for proper interpretation of SCN5A genetic testing and provides an essential hit list of targets for future functional studies to determine whether or not any of these variants mediate genetic susceptibility for arrhythmias in the setting of either drugs or disease.
Assuntos
Frequência do Gene , Polimorfismo Conformacional de Fita Simples , Grupos Raciais/genética , Canais de Sódio/genética , Bloqueio de Ramo/genética , Cromatografia Líquida de Alta Pressão , Análise Mutacional de DNA , Éxons , Predisposição Genética para Doença , Humanos , Síndrome do QT Longo/genética , Mutação de Sentido Incorreto , Canal de Sódio Disparado por Voltagem NAV1.5 , Síndrome , Fibrilação Ventricular/genéticaRESUMO
Every year, approximately 450,000 individuals in the United States die suddenly of cardiac arrhythmia. We identified a variant of the cardiac sodium channel gene SCN5A that is associated with arrhythmia in African Americans (P = 0.000028) and linked with arrhythmia risk in an African-American family (P = 0.005). In transfected cells, the variant allele (Y1102) accelerated channel activation, increasing the likelihood of abnormal cardiac repolarization and arrhythmia. About 13.2% of African Americans carry the Y1102 allele. Because Y1102 has a subtle effect on risk, most carriers will never have an arrhythmia. However, Y1102 may be a useful molecular marker for the prediction of arrhythmia susceptibility in the context of additional acquired risk factors such as the use of certain medications.