br Voltage gated sodium channels
Voltage-gated sodium src inhibitor are essential for modulating the amplitude and upstroke velocity of the cardiac action potential, which are parameters that are important determinants of impulse propagation and conduction velocity through the myocardium. Functional analyses using patch-clamp techniques in a heterologous expression system demonstrated that most of the SCN5A mutations had a loss-of-function effect, primarily manifested as a failure of intracellular trafficking to the cell membrane or malfunction of gating kinetics [12–15]. Surprisingly, SCN5A mutations are associated with different phenotypes, in addition to BrS, even among members of the affected family (Fig. 1). These phenotypes include long QT syndrome (type 3) [16–21], progressive cardiac conduction defects [22–25], sick sinus syndrome [26–29], familial atrial fibrillation [30–32], early repolarization syndrome , dilated cardiomyopathy [34–36], and sudden infant death syndrome [37–39]. Very recently, a French research group reported an SCN5A R222Q mutation in 3 unrelated families with multifocal ectopic Purkinje-related premature contractions (MEPPC) and demonstrated that the mutation caused a gain-of-function of the cardiac sodium channel . Even in a single patient, these phenotypes can overlap (so-called overlap syndrome). Characteristic clinical features differentiate the SCN5A-related BrS from other forms of BrS and can help predict the genetic diagnosis of BrS. The appearance of overlap phenotypes seems to be mutation-specific. For example, the SCN5A E1784K mutant has been linked to not only BrS but also long QT and familial sick sinus syndrome . Though they are the most studied among BrS-associated genes, SCN5A genotype–BrS phenotype correlations remain controversial. According to numerous functional assays, there is convincing data for the hypothesis that the biophysical effects of SCN5A mutations identified in BrS patients account for their phenotype. However, in extensive surveys of family members, SCN5A mutations were also identified in phenotype-negative individuals . On the contrary, in a study on 13 BrS families containing ≥5 BrS patients , 8 individuals presented with typical type 1 BrS who lacked SCN5A mutations. Taken together, these data suggest that mutations in SCN5A alone do not directly cause but work as modifiers to increase the likelihood of developing the BrS phenotype in some BrS patients.
In 2002, the second candidate locus of BrS was discovered on chromosome 3p22-25 in a large Italian family by using linkage analysis . The sodium channel genes located on that locus, SCN5A, SCN10A, and SCN12A, on chromosome 3 were excluded as candidates in the family. Therefore, London et al.  further searched and narrowed the BrS-associated region to 1millionbp on chromosome 3p24. Although 4 known genes were located on this region, they were eliminated by single-strand conformational polymorphism (SSCP) and/or direct sequencing. In the linkage region, RNA from 2 genes of unknown function in the heart was identified using reverse-transcriptional polymerase chain reaction (PCR) and direct sequencing. Finally, a missense mutation was detected in one of the genes. The gene was GPD1L (NM_015141), and the mutation was a C/T base-pair change (C899T) leading to an alanine-to-valine substitution at amino acid 280 (A280V). The co-expression of SCN5A and GPD1L-A280V, but not SCN5A and wild-type (WT) GPD1L, in human embryonic kidney (HEK) cells significantly changed the amplitude of INa. The data also showed that the trafficking deficiency of Nav1.5 to the cell surface was the underlying mechanism responsible for decreased INa. Following this report, 3 novel GPD1L mutations, corresponding to E83K, I124V, and R273C in GPD1L protein, were identified in 304 cases of sudden infant death syndrome . In the functional analyses, all mutant channels showed a reduction in the INa current. A study on 80 Japanese BrS patients in Asia by Makiyama and his colleagues did not identify any GPD1L mutations . The relevance of GPD1L mutations in Asian BrS patients needs further study.