Ambigous phenotipic expression of some mutations in the cardiac Nav1.5 sodium channel

Abstract

Introduction Inherited cardiac arrhythmic syndromes are among the most studied human disorders involving ion channels. Since 1995, hundreds of mutations have been found in more than twenty genes coding for cardiac ion channel subunits or proteins regulating cardiac ion channels. The main ECG syndromes caused by those mutations are outlined but there are many mixed and intermediate phenotypes. The phenotype-genotype correlations are not well understood but expected to be related to a functional effect on the ion conductivity. Material and methods Clinical examination including family history taking, ECG, 24-h Holter monitoring, and pharmacological testing with Na + -blockers (by indication) was performed for 192 families with suspected primary arrhythmic syndromes. Diagnoses were established using conventional criteria. Genetic screening of KCNQ1 , KCNE1 , KCNH2 , KCNE2 , KCNJ2 , KCNE3 , SCN5A , and SCN1B-SCN4B was performed for 192 probands by bi-directional Sanger sequencing. Phenotype-genotype correlations had been analyzed. Results and discussion Totally we had found 58 mutations in the genes encoding potassium channels (39 in the KCNQ1 gene, 14 in the KCNH2 gene, 2 in the KCNE1 gene, 1 in the KCNE2, and 1 in the KCNJ2 gene) and 23 mutations in the genes encoding sodium channels (22 in the SCN5A and 1 on the SCN1B). Most of mutations were found in a single family. Patients caring two mutations had more sever clinical appearance of cardiac arrhythmia and high risk of cardiac sudden death. We had found 5 mutations encoding sodium channel mutations (4 in the SCN5A gene and 1 in the SCN1B gene), which lead to the different and sometimes opposite phenotypes in different probands (LQTS and/or BrS, IVF, various cardiomyopathies) or even within the same family members. This phenomenon was not observed in clinical expression of the potassium channel mutations. All mutations found in the genes encoding potassium channels subunits had univocal and predictable phenotype. Mutations leading to the haplo-insufficiency or “loss-of-function” of the potassium channels had caused Long QT Syndrome; “gain-of-function” mutations were responsible for Short QT Syndrome and/or Brugada Syndrome. Conclusion Despite the fairly detailed biophysical characterizations of the mutant variants of Nav1.5 protein, the stages of the molecular pathogenesis leading from the disruption of sodium conductance to the clinical phenotype are not fully understood. «Non-canonical» functions of the Nav1.5 channel beside ion conductance might be crucial for the resulting clinical appearance.