Congenital long-QT syndrome (LQTS) and Brugada syndrome (BrS) are cardiac channelopathies caused by mutations in cardiac ion channel genes. LQTS is characterized by excitability and prolonged repolarization, abnormal T wave morphology, and cardiac arrhythmias; in BrS it is observed ST segment elevation, right bundle branch block and susceptibility to ventricular tachyarrhythmia during rest or sleep. Supraventricular tachyarrhythmias are common finding in both patients. LQTS is caused by mutations in KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 genes; BrS is caused, in 10-20% of cases, by mutations in SCN5A gene. We determined the spectrum of cardiac channel mutations in a cohort of unrelated Southern Italy. We screened KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 genes FOR 26 unrelated LQTS patients and only SCN5A gene for 30 unrelated BrS patients. To screen, we use the PCR, dHPLC and DNA sequencing. We than expressed in HEK 293 cells, 5 unknown variants SCN5A: c.T1808C, c.G3964T, c.C3989A and c.4414_4416delAAC (LQTS) and c.G2284A (BrS). The FITC-antibody was used to locate these mutants.
 We found 19 disease-causing mutations in the 26 unrelated LQTS families (73%): c.G5349A in SCN5A in 3 patients, c.C1682T and c.T2414C in KCNH2, and c.C691T, c.A842G, c.T910C, c.G1032A, c.G1573A and c.G1748A in KCNQ1, which are known mutations; c.T1808C, c.4414_4416delAAC, c.G3964T, and c.C3989A in SCN5A, c.G323A and c.1450_1467del in KCNH2, c.824_826delTCt in KCNQ1 and c.C29T in KCNE1, which are novel mutations. In the 30 BrS patients we found e mutations in SCN5A: c.C647T and c.C1099T which are known mutations, and c.G2284A, an unknown mutation. All mutations co-segregated with the disease in the affected families. Immunocytochemistry showed that all variants are located to the cell surface. Functional characterization of these variants is underway using the voltage-clamp technique. 
 About 73% of our LQTS patients had a mutation: about half of the mutations are novel; 10% of our BrS patients shows a mutation in SCN5A. Screening of cardiac ion channel genes may: i) facilitate causative analysis at gene level in LQTS patients, and ii) identify carriers of gene mutations with reduced penetrance, thereby reducing the risk of sudden death.

Cardiac ion channel genes analysis in LQTS or Brugada families of Southern Italy revealed nineteen mutations, including nine novel ones

FRISSO, GIULIA;DETTA, NICOLA;BONADUCE, DOMENICO;SALVATORE, FRANCESCO
2009

Abstract

Congenital long-QT syndrome (LQTS) and Brugada syndrome (BrS) are cardiac channelopathies caused by mutations in cardiac ion channel genes. LQTS is characterized by excitability and prolonged repolarization, abnormal T wave morphology, and cardiac arrhythmias; in BrS it is observed ST segment elevation, right bundle branch block and susceptibility to ventricular tachyarrhythmia during rest or sleep. Supraventricular tachyarrhythmias are common finding in both patients. LQTS is caused by mutations in KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 genes; BrS is caused, in 10-20% of cases, by mutations in SCN5A gene. We determined the spectrum of cardiac channel mutations in a cohort of unrelated Southern Italy. We screened KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 genes FOR 26 unrelated LQTS patients and only SCN5A gene for 30 unrelated BrS patients. To screen, we use the PCR, dHPLC and DNA sequencing. We than expressed in HEK 293 cells, 5 unknown variants SCN5A: c.T1808C, c.G3964T, c.C3989A and c.4414_4416delAAC (LQTS) and c.G2284A (BrS). The FITC-antibody was used to locate these mutants.
 We found 19 disease-causing mutations in the 26 unrelated LQTS families (73%): c.G5349A in SCN5A in 3 patients, c.C1682T and c.T2414C in KCNH2, and c.C691T, c.A842G, c.T910C, c.G1032A, c.G1573A and c.G1748A in KCNQ1, which are known mutations; c.T1808C, c.4414_4416delAAC, c.G3964T, and c.C3989A in SCN5A, c.G323A and c.1450_1467del in KCNH2, c.824_826delTCt in KCNQ1 and c.C29T in KCNE1, which are novel mutations. In the 30 BrS patients we found e mutations in SCN5A: c.C647T and c.C1099T which are known mutations, and c.G2284A, an unknown mutation. All mutations co-segregated with the disease in the affected families. Immunocytochemistry showed that all variants are located to the cell surface. Functional characterization of these variants is underway using the voltage-clamp technique. 
 About 73% of our LQTS patients had a mutation: about half of the mutations are novel; 10% of our BrS patients shows a mutation in SCN5A. Screening of cardiac ion channel genes may: i) facilitate causative analysis at gene level in LQTS patients, and ii) identify carriers of gene mutations with reduced penetrance, thereby reducing the risk of sudden death.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/376065
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