RESUMO
BACKGROUND: Loss-of-function mutations in the KCNJ2 cause approximately 50% of Andersen-Tawil Syndrome (ATS) characterized by a classic triad of periodic paralysis, ventricular arrhythmia, and dysmorphic features. Do KCNJ2 mutations occur in patients lacking this triad and lacking a family history of ATS? OBJECTIVES: The purpose of this study was to identify and characterize mutations in the KCNJ2-encoded inward rectifier potassium channel Kir2.1 from patients referred for genetic arrhythmia testing. METHODS: Mutational analysis of KCNJ2 was performed for 541 unrelated patients. The mutations were made in wild type (WT) and expressed in COS-1 cells and voltage clamped for ion currents. RESULTS: Three novel missense mutations (R67Q, R85W, and T305A) and one known mutation (T75M) were identified in 4/249 (1.6%) patients genotype-negative for other known arrhythmia genes with overall incidence 4/541 (0.74%). They had prominent U-waves, marked ventricular ectopy, and polymorphic ventricular tachycardia but no facial/skeletal abnormalities. Periodic paralysis was present in only one case. Outward current was decreased to less than 5% of WT for all mutants expressed alone. Co-expression with WT (simulating heterozygosity) caused a marked dominant negative effect for T75M and R82W, no dominant negative effect for R67Q, and a novel selective enhancement of inward rectification for T305A. CONCLUSIONS: KCNJ2 loss of function mutations were found in approximately 1% of patients referred for genetic arrhythmia testing that lacked criteria for ATS. Characterization of three new mutations identified a novel dominant negative effect selectively reducing outward current for T305A. These results extend the range of clinical phenotype and molecular phenotype associated with KCNJ2 mutations.
Assuntos
Testes Genéticos , Síndrome do QT Longo/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Idoso , Arritmias Cardíacas/genética , Criança , Pré-Escolar , Técnicas Eletrofisiológicas Cardíacas , Feminino , Expressão Gênica , Predisposição Genética para Doença , Genótipo , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fenótipo , Canais de Potássio Corretores do Fluxo de Internalização , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Taquicardia Ventricular/genéticaRESUMO
BACKGROUND: Mutations in the RyR2-encoded cardiac ryanodine receptor/calcium release channel and in CASQ2-encoded calsequestrin cause catecholaminergic polymorphic ventricular tachycardia (CPVT1 and CPVT2, respectively). OBJECTIVES: The purpose of this study was to evaluate the extent of genotypic and phenotypic heterogeneity among referrals for CPVT genetic testing. METHODS: Using denaturing high-performance liquid chromatography and DNA sequencing, mutational analysis of 23 RyR2 exons previously implicated in CPVT1, comprehensive analysis of all translated exons in CASQ2 (CPVT2), KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), KCNE2 (LQT6), and KCNJ2 (Andersen-Tawil syndrome [ATS1], also annotated LQT7), and analysis of 10 ANK2 exons implicated in LQT4 were performed on genomic DNA from 11 unrelated patients (8 females) referred to Mayo Clinic's Sudden Death Genomics Laboratory explicitly for CPVT genetic testing. RESULTS: Overall, putative disease causing mutations were identified in 8 patients (72%). Only 4 patients (3 males) hosted CPVT1-associated RyR2 mutations: P164S, V186M, S3938R, and T4196A. Interestingly, 4 females instead possessed either ATS1- or LQT5-associated mutations. Mutations were absent in >400 reference alleles. CONCLUSION: Putative CPVT1-causing mutations in RyR2 were seen in <40% of unrelated patients referred with a diagnosis of CPVT and preferentially in males. Phenotypic mimicry is evident with the identification of ATS1- and LQT5-associated mutations in females displaying a normal QT interval and exercise-induced bidirectional VT, suggesting that observed exercise-induced polymorphic VT in patients may reflect disorders other than CPVT. Clinical consideration for either Andersen-Tawil syndrome or long QT syndrome and appropriate genetic testing may be warranted for individuals with RyR2 mutation-negative CPVT, particularly females.
Assuntos
Catecolaminas/metabolismo , DNA/genética , Testes Genéticos/métodos , Mutação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/genética , Adolescente , Adulto , Criança , Cromatografia Líquida de Alta Pressão , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Genótipo , Humanos , Masculino , Fenótipo , Estudos RetrospectivosRESUMO
The Na current (I(Na)) in human ventricle is carried through a specific isoform of the voltage gated Na channel in heart. The pore forming alpha-subunit is encoded by the gene SCN5A. Up to four beta-subunits may be associated, and the larger macromolecular complex may include attachments to cytoskeleton and scaffolding proteins, all of which may affect the gating kinetics of the current. I(Na) underlies initiation and propagation of action potentials in the heart and plays a prominent role in cardiac electrophysiology and arrhythmia. In addition, I(Na) also loads the ventricular cell with Na(+) ions and plays an important role in intracellular Na homeostasis. This review considers the structure and function of the human cardiac Na channel that carries I(Na) with a particular consideration of the implications of alterations in I(Na) in acquired cardiac diseases such as hypertrophy, failure, and ischemia, which affect Na loading.