900 KURAKAMI K et al. Circulation Journal EDITORIAL Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Is a Novel SCN3B Mutation Commonly Found in SCN5A-Negative Patients? Kazuya Kurakami, MD; Kuniaki Ishii, MD, PhD

udden cardiac death (SCD) is a tragic event that can are not mutually exclusive, point to right ventricular altera- occur even among apparently healthy patients with no tions involving either early repolarization or late activation. S structural heart disease. SCD in the absence of an iden- These electrophysiological alterations can be brought about by tifiable cause has been considered to be due to idiopathic genetic disorders of cardiac ion channels. ventricular fibrillation (IVF). However, by virtue of progress in molecular genetics, it is increasingly recognized that ion Article p 959 channel mutations may underlie many cases previously regard- ed as IVF.1 Brugada syndrome (BS) is 1 such channelopathies BS was first described in 1992 by Brugada and Brugada.4 and has been identified as the same entity, previously called In 1998, Chen et al reported the first BS mutations in SCN5A, sudden unexpected nocturnal death syndrome, found in South- the encoding the α-subunit of the cardiac Na+ channel east Asian countries, including Japan.2 BS is characterized by (Nav1.5).5 These mutations lead to loss-of-function pheno- ST-segment elevation with a “coved” morphology in the right types by altering Nav1.5 cell surface expression or modifying precordial leads (V1–3) and right bundle branch block, and is its gating properties, and are the major cause of BS. To date, associated with SCD resulting from episodes of VF.3 Although almost 300 SCN5A mutations have been linked to BS.6 How- the pathophysiological mechanisms underlying the BS pheno- ever, because SCN5A mutations account for only 11–28% of type are not completely understood, 2 hypotheses have been BS cases, extensive investigations for other responsible proposed to explain the ST segment alterations in BS patients: have been and are being carried out. So far, 12 more BS-sus- depolarization and repolarization theories.3 Both models, which ceptible genes have been identified,7,8 2 of which are genes en-

Figure. Genes linked to Brugada syndrome (BS). Prevalence of SCN5A mutations in BS patients is 11–28%, and that of SCN3B mutation, V110I, in SCN5A-neg- ative BS patients is approximate- ly 10%. SCN3B mutations found in BS are marked with red circles on Navβ3. Impaired trafficking of Nav1.5 is the mechanism by which V110I reduces the Na+ current (INa).

The opinions expressed in this article are not necessarily those of the editors or of the Japanese Circulation Society. Received February 18, 2013; accepted February 18, 2013; released online March 1, 2013 Department of Pharmacology, Yamagata University School of Medicine, Yamagata, Japan Mailing address: Kuniaki Ishii, MD, PhD, Department of Pharmacology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-13-0242 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Circulation Journal Vol.77, April 2013 Prevalence and Significance of Novel SCN3B Mutation 901 coding the β-subunit of the Na+ channel (SCN1B and SCN3B), lence of other BS-susceptible genes are reported to be very and 2 are genes encoding that functionally or physi- low.3 However, the SCN3B mutation V110I was found in ap- cally interact with the Na+ channel (GPD1L and MOG1). The proximately 10% familial cases and approximately 0.6% spo- other identified genes encode the cardiac L-type Ca2+ channel radic cases of SCN5A-negative BS patients. In 2011, 2 expert (CACNA1C, α-subunit; CACNB2B, β-subunit; CACNA2D1, consensus statements were published on the use of genetic α2/δ-subunit), the transient outward K+ channel (KCND3, testing for channelopathies and cardiomyopathies: from the α-subunit; KCNE3, β-subunit; KCNE5, β-subunit), the ATP- Heart Rhythm Society/the European Heart Rhythm Associa- sensitive K+ channel (KCNJ8), and the If channel (HCN4) tion,14 and from the Canadian Cardiovascular Society/Canadian (Figure). Disease-causing mutations of these proteins either Heart Rhythm Society.15 The former states that comprehen- decrease depolarizing inward currents (INa, ICa,L and If) or in- sive or SCN5A-specific genetic testing can be useful for any crease repolarizing outward currents (Ito and IKATP). Each of BS patient. The latter states that genetic testing should be these 12 genes is responsible for less than 1% of BS cases. limited to analysis of SCN5A and considered for other BS- In humans, fiveβ -subunits (Navβ1, Navβ1b (a splice vari- responsible genes only under special circumstances. The rela- ant), Navβ2, Navβ3, and Navβ4, encoded by SCN1B to SCN4B) tively high prevalence of the SCN3B mutation V110I reported have been identified, which associate with theα -subunit of by Ishikawa et al suggests the usefulness of SCN3B-targeted Na+ channels.9 With the exception of Navβ1b, they share a genetic testing especially for SCN5A-negative Japanese BS similar membrane topology, having a large extracellular N- patients with familial history. Future study in a large cohort terminal domain with an immunoglobulin loop, 1 transmem- will help answer this question. brane domain, and a small intracellular C-terminal domain. In addition to modulation of Na+ channel expression and func- References tion, β-subunits have been suggested to play other roles, in- 1. Napolitano C, Bloise R, Monteforte N, Priori SG. Sudden cardiac cluding cell adhesion, signal transduction and recruitment of death and genetic ion channelopathies: Long QT, Brugada, short QT, anchoring proteins.10 Obviously, -subunits play an important catecholaminergic polymorphic ventricular tachycardia, and idio- β pathic ventricular fibrillation. Circulation 2012; 125: 2027 – 2034. role in cardiac excitability, because many genetic variants of 2. Vatta M, Dumaine R, Varghese G, Richard TA, Shimizu W, Aihara N, β-subunits are found in various electrophysiological disorders et al. Genetic and biophysical basis of sudden unexplained nocturnal of the heart.11 death syndrome (SUNDS), a disease allelic to Brugada syndrome. In this issue of the Journal, Ishikawa et al report a novel Hum Mol Genet 2002; 11: 337 – 345. 3. Berne P, Brugada J. Brugada syndrome 2012. Circ J 2012; 76: 1563 – SCN3B mutation in Japanese BS patients who were negative 1571. 12 + for SCN5A mutations. SCN3B encodes the Na channel 4. Brugada P, Brugada J. Right bundle branch block, persistent ST seg- Navβ3 subunit that modulates cell surface expression and ment elevation and sudden cardiac death: A distinct clinical and elec- function of the Nav1.5 channel. The mutation they identified trocardiographic syndrome: A multicenter report. J Am Coll Cardiol 1992; 20: 1391 – 1396. was V110I, which caused a reduction of INa through impair- 5. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, et al. ment of Nav1.5 trafficking to the plasma membrane. This is Genetic basis and molecular mechanism for idiopathic ventricular the second SCN3B mutation identified in BS patients. In 2009, fibrillation.Nature 1998; 392: 293 – 296. Hu et al reported the first SCN3B mutation, L10P, in a Caucasian 6. Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, male with a type 1 BS ECG.13 The L10P mutation also impairs et al. An international compendium of mutations in the SCN5A-en- coded cardiac in patients referred for Brugada syn- Nav1.5 trafficking to the plasma membrane, leading to re- drome genetic testing. Heart Rhythm 2010; 7: 33 – 46. duced INa current. The trafficking defect induced by these 7. Veerakul G, Nademanee K. Brugada syndrome: Two decades of prog- mutations was not related to disruption of the association of ress. Circ J 2012; 76: 2713 – 2722. Nav1.5 and the Nav 3 subunit, which suggested abnormal 8. Ueda K, Hirano Y, Higashiuesato Y, Aizawa Y, Hayashi T, Inagaki N, β et al. Role of HCN4 channel in preventing ventricular arrhythmia. J retention of the Navβ3 mutants in the endoplasmic reticulum Hum Genet 2009; 54: 115 – 121. (ER). Thus, normal trafficking of the Na+ channel may be re- 9. Meadows LS, Isom LL. Sodium channels as macromolecular com- stored if the Navβ3 mutants abnormally retained in the ER are plexes: Implications for inherited arrhythmia syndromes. Cardiovasc rescued by drugs etc. Res 2005; 67: 448 – 458. 10. Abriel H. Cardiac sodium channel Nav1.5 and interacting proteins: When coexpressed with Nav1.5 in tsA-201 cells, Navβ3- Physiology and pathophysiology. J Mol Cell Cardiol 2010; 48: 2 – L10P slowed recovery from inactivation of the Na+ channel, 11. whereas the novel V110I mutation had little effect on the 11. Amin AS, Asghari-Roodsari A, Tan HL. Cardiac sodium channelo- biophysical properties of the Na+ channel.12 However, the pathies. Pflügers Arch 2010; 460: 223 – 237. electrophysiological changes induced by Nav 3-L10P were 12. Ishikawa T, Takahashi N, Ohno S, Sakurada H, Nakamura K, On YK, β et al. Novel SCN3B mutation associated with Brugada syndrome not the same when Navβ1 was included together with Nav1.5: affects intracellular trafficking and function of Nav1.5. Circ J 2013; additional acceleration of inactivation and negative shift of 77: 959 – 967. steady-state inactivation curve were observed,13 which indi- 13. Hu D, Barajas-Martinez H, Burashnikov E, Springer M, Wu Y, Varro cates that the phenotype induced by SCN3B mutations can be A, et al. A mutation in the β3 subunit of the cardiac sodium channel associated with Brugada ECG phenotype/clinical perspective. Circ influenced by anotherβ -subunit Navβ1. It is also known that Cardiovasc Genet 2009; 2: 270 – 278. heterologous expression of SCN3B yields discrepant results,10 14. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, which may be related to differences in other modifying pro- et al. HRS/EHRA expert consensus statement on the state of genetic teins in different expression systems. Although the contribu- testing for the channelopathies and cardiomyopathies: This docu- ment was developed as a partnership between the Heart Rhythm tion of other modifying proteins may make it hard to fully Society (HRS) and the European Heart Rhythm Association (EHRA). understand BS caused by β-subunit mutations, the novel SCN3B Heart Rhythm 2011; 8: 1308 – 1339. mutation V110I is probably a relatively common cause in 15. Gollob MH, Blier L, Brugada R, Champagne J, Chauhan V, Connors Japanese BS patients. S, et al. Recommendations for the use of genetic testing in the clini- cal evaluation of inherited cardiac arrhythmias associated with sud- As stated before, loss-of-function mutations in the SCN5A- den cardiac death: Canadian Cardiovascular Society/Canadian Heart coded α-subunit represent the most common genetic disorders, Rhythm Society joint position paper. Can J Cardiol 2011; 27: 232 – accounting for 11–28% of all BS cases, whereas the preva- 245.

Circulation Journal Vol.77, April 2013