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  • br A KCNJ mutation corresponding

    2019-06-10


    A KCNJ8 mutation, corresponding to an S422L mutation in the protein, was first identified in a 14-year-old girl with early repolarization [59], who suffered frequent VF attacks. KCNJ8 encodes Kir6.1, which has 2 transmembrane regions, and the KATP channel is composed of a complex of Kir6.1 or Kir6.2 and the sulfonylurea receptor (SUR) [60]. In a subsequent report, 87 BrS patients were genetically screened for changes in KCNJ8 and one asymptomatic BrS patient was identified with the S422L mutation [61]. A coved-type ST elevation in ECG evaluations of this patient was unmasked after flecainide administration. To confirm the functional effect of the S422L mutation, glibenclamide-sensitive KATP currents were recorded in retinoic acid receptor co-expressing Kir6.1 and SUR2. The results showed that KATP current density of Kir6.1-S422L mutant channels was remarkably increased compared to that of the Kir6.1-WT channels.
    KCND3 encodes Kv4.3, which is the α subunit of the potassium channel that modulates Ito. The differences of Ito densities between the endocardium and epicardium, or the increase of Ito in the epicardium have been discussed as mechanisms underlying BrS [62]. Therefore, KCND3 was expected to be a strong candidate gene, and indeed, 2 KCND3 mutation carriers were identified from 86 BrS patients in whom no mutations were detected in other reported BrS genes [63]. The first patient with the Kv4.3-L450F mutation was a 45-year-old man with a history of heart palpitations at rest. His ECG showed slight ST elevation; therefore, he underwent a flecainide challenge test that induced a type 1 ECG pattern. Another patient with the Kv4.3-G600R mutation was a 22-year-old man with a history of heart palpitations and pre-syncope. He was discovered unconscious and unresponsive in bed. The 12-lead ECG examination conducted after hospitalization revealed ST segment elevation in V1, V2, and V3. In the functional analysis of the mutants in cells, co-expression of both Kv4.3 mutants with KChip2 increased the Ito densities, and the deactivation time constant of the Kv4.3-G600R channel was slower than that of the WT. Computer simulations revealed that both Kv4.3 mutations caused a loss of the action potential dome of reconstituted right ventricular (RV) epicardial action potentials.
    MOG1 is a recently identified protein that modifies the expression and trafficking of Nav1.5 [64]. A MOG1-E83D mutation was identified in a 40-year-old woman who was resuscitated from cardiac arrest [65]. Her ECG showed ST elevation and an atypical right branch block just after the resuscitation. The ST elevation was normalized 24h later. The functional analysis of MOG1-E83D by using patch-clamp methods showed decreased INa, and expression of the mutant in cells decreased the levels of Nav1.5 on the cell membrane.
    Recently, 2 mutations in SLMAP were reported to cause BrS [66]. SLMAP encodes sarcolemmal membrane-associated protein (SLMAP) that localizes at T-tubules. The functions of SLMAP have not been well elucidated. The mutations, V269I and E710A, were identified in a 46-year-old and a 57-year-old male patient, respectively, and both of them experienced syncope and showed spontaneous saddle-back (V269I) or coved-type (E710A) ST elevation. To elucidate the functional effect of SLMAP mutations on the cardiac INa, SLMAP-WT or mutants were co-expressed with NaV1.5. The results showed that INa in cells co-expressing SLMAP-V269I or −E710A with NaV1.5 were significantly lower than that co-expressing the WT protein. Moreover, membrane surface expression of Nav1.5 was impaired in cells harboring the mutant SLMAP.
    More recently, another β subunit of the sodium channel, SCN2B, was reported to be a candidate gene involved in BrS [67]. Three mutations, corresponding to R28Q, –Y69H and –P210L in the β2 subunit, were identified in 4 patients from a survey of 269 BrS patients. In the functional analysis, INa in cells with the mutant β2 were decreased compared to those with the WT protein, and all the mutants perturbed normal trafficking of Nav1.5 to the membrane.