Editorial To Be or Not to Be Long-QT Syndrome Type 9 Michael J Cutler, DO, PhD; Elizabeth S. Kaufman, MD

C

ongenital long-QT syndrome (LQTS) is a rare heritable disorder that is associated with a high risk of syncope and sudden cardiac death. Since 1996, LQTS has been categorized based on mutations to genes that encode cardiac ion channel subunits or proteins that modulate ionic currents in the heart. The most common LQTS gene mutations involve KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3). Multiple other rare gene mutations have been identified and postulated to cause LQTS (LQT4–LQT13). However, in some cases, the identified mutations are part of a more complex clinical disorder (ie, LQT7 and LQT8) and may not be part of the LQTS in the classical sense. In other cases, such as LQT9, there are limited data supporting a causative link between a mutation and LQTS.

Article see p 452 The CAV3 gene encodes an integral membrane protein called caveolin 3. Caveolins play an important role in signal transduction and vesicular transport within cells. Mutations to CAV3 have been found to cause diseases of both skeletal and cardiac muscle. Furthermore, mutations to CAV3 were recently identified as rare, potentially disease-causing mutations in a series of patients referred for LQTS genetic testing.1 In 2006, Vatta et al1 reported finding 1 of 4 novel CAV3 mutations (T78M, A85T, F97C, and S141R) in 6 (0.7%) of 904 unrelated patients. Cellular electrophysiological characterization of 2 of these mutations (F97C and S141R) revealed that the mutations resulted in as much as a 4-fold increase in the late sodium current (INaL). Based on the recognition that multiple ion channels and transporters have been localized to caveolae, and that caveolin 3 interacts with various signaling molecules, the authors speculated that “modulation of other ion channels or signaling pathways regulating ionic currents also may contribute to the pathophysiology (of the QT prolongation).” In fact, prior and subsequent studies have shown that caveolin 3 is involved in the increase in INaL that occurs during β-adrenergic stimulation.2–4 In 2007, Cronk et al5 reported detecting CAV3 mutations (V14L, T78M, and L79R) The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Heart & Vascular Center, MetroHealth Campus of Case Western Reserve University, Cleveland, OH. Correspondence to Elizabeth S. Kaufman, MD, Heart & Vascular Center, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Dr, Hamann 3, Cleveland, OH 44109-1998. E-mail [email protected] (Circ Cardiovasc Genet. 2013;6:439-440.) © 2013 American Heart Association, Inc. Circ Cardiovasc Genet is available at http://circgenetics.ahajournals.org DOI: 10.1161/CIRCGENETICS.113.000345

in cases of sudden infant death syndrome. Functional analysis of these mutations also demonstrated significant increase in INaL. More recently, Cheng et al6 showed that the F97C CAV3 mutation alters the activity of neuronal NO synthase 1 on the cardiac sodium channel (SCN5A). Specifically, this mutation was shown to remove the repressive effect of caveolin on NO synthase 1, resulting in increased S-nitrosylation of SCN5A and a concomitant increase in INaL. Other studies have pointed to important interactions between caveolin 3 and potassium channel function. KCNH2 expression in the membrane (and thus IKr current) is regulated by caveolin 3.7 Mutations of CAV3 reduce cell surface expression of Kir2.1 (IK1 current).8 In addition, caveolins are involved in low K+o-induced degradation of mature IKr channels.9 Although these data suggest plausible mechanisms for LQTS in individuals with CAV3 mutations, the clinical data supporting CAV3 mutations as pathogenic, particularly T78M, are sparse. In Vatta et al’s initial report,1 T78M was seen in 3 patients, 1 of whom had a concomitant known LQT2 mutation. The 3 patients had normal or at most modestly prolonged QT intervals. One was asymptomatic, and 2 (both with sinus bradycardia) had nonexertional syncope. In this issue of Circulation: Cardiovascular Genetics, Hedley et al10 screened a series of LQTS probands (n=167) for mutations in the CAV3 gene. The authors identified a single case (0.6%) of CAV3 mutation in this population, specifically the T78M mutation. Importantly, the proband was also a carrier of a KCNH2 (LQT2) mutation. Subsequently, the authors screened the family of the affected proband and identified 6 family members with the T78M CAV3 mutation. Similar to the proband, 3 of the 6 family members with the T78M CAV3 mutation also had a KCNH2 (LQT2) mutation; these 3 individuals had QT prolongation (QTc ≥470 ms), and 2 of the 3 had a history of syncope. This phenotype was consistent with clinical LQTS and was not more severe than the phenotype of family members with the LQT2 mutation alone. In contrast, the 3 family members carrying only the T78M CAV3 mutation had normal QT intervals (QTc, 410– 420 ms). Although all 3 had a history of syncope, it was not exertional syncope. The authors describe that 1 of these was an elderly woman with marked PR prolongation, 1 had syncope associated with a painful delivery, and 1 had syncope associated with a painful accident. Although these episodes may not represent classic LQTS-related exertional syncope, 2 of the episodes occurred during adrenergic stimulation. It is interesting to recall that Vatta et al1 reported on a 13-year-old patient with asthma with the F97C CAV3 mutation whose QT prolongation was absent at rest but reproducibly present on β-agonist therapy for her asthma.

Downloaded from http://circgenetics.ahajournals.org/ 439 at MCMASTER UNIV on March 23, 2015

440  Circ Cardiovasc Genet  October 2013 Based on the borderline phenotypic evidence for LQTS in Vatta et al’s report1 and in their own study, Hedley et al10 concluded that T78M CAV3 mutations in isolation cannot be considered LQTS disease-causing mutations. Furthermore, Hedley’s group conducted functional studies and concluded that although caveolin interacts with Kv11.1 (encoded by KCNH2), the T78M CAV3 mutation in isolation alters neither the interaction between caveolin and Kv11.1 nor the Kv11.1 current. Although they acknowledge Cronk et al’s5 demonstration of a marked increase in INaL with T78M, they assert that it is “meaningless to assess the effects CAV3 mutations have on a single ion channel without being able to assess the effect on the action potential as a whole.” The authors allow that CAV3 mutations may have highly variable phenotypic expression but recommend that LQT9 be considered a provisional entity. Can CAV3 mutations cause LQTS? Can we conclude that they do not? It is always difficult to know with certainty which rare genetic variants are disease-causing. Let us consider the points on which Hedley et al10 base their argument. First, the small number of patients with T78M did not have significant resting QTc prolongation. This, in itself, is not sufficient to discount T78M as a LQTS susceptibility mutation. The literature is full of examples of individuals with known pathogenic LQTS mutations and normal phenotype. In some studies, penetrance has been estimated to be only 25%.11 The absence of resting QTc prolongation among affected individuals has given rise to the common use of provocative testing with exercise and epinephrine to unmask latent LQTS because patients with normal resting QTc may still be at risk of syncope and sudden cardiac death during adrenergic stimulation.12 Furthermore, there are mutations (and even polymorphisms) that tend to be silent until a second condition (bradycardia, hypokalemia, addition of a drug) arises. However, in some patients, these same mutations are disease-causing without the presence of a second condition.13 So, an absence of resting QTc prolongation in a small sample size (n=6) cannot exclude T78M as a pathogenic mutation. What about the cellular expression data? The authors of the current study agree that teasing out the effect of a mutation on the action potential as a whole is complex and cannot be solved by studies of individual ion channel function in isolation. This provocative study by Hedley et al10 does not eliminate LQT9 as a diagnostic entity. However, it clearly sets the stage for further investigation to elucidate the mechanisms underlying LQT9. Future studies using inducible

pluripotent stem cell technology seem ideal for helping to resolve the question of whether LQT9 is to be or not to be.

Disclosures None.

References 1. Vatta M, Ackerman MJ, Ye B, Makielski JC, Ughanze EE, Taylor EW, et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation. 2006;114:2104–2112. 2. Yarbrough TL, Lu T, Lee HC, Shibata EF. Localization of cardiac sodium channels in caveolin-rich membrane domains: regulation of sodium current amplitude. Circ Res. 2002;90:443–449. 3. Lu T, Lee HC, Kabat JA, Shibata EF. Modulation of rat cardiac sodium channel by the stimulatory G protein alpha subunit. J Physiol. 1999;518 (pt 2):371–384. 4. Palygin OA, Pettus JM, Shibata EF. Regulation of caveolar cardiac sodium current by a single Gsalpha histidine residue. Am J Physiol Heart Circ Physiol. 2008;294:H1693–H1699. 5. Cronk LB, Ye B, Kaku T, Tester DJ, Vatta M, Makielski JC, et al. Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3. Heart Rhythm. 2007;4:161–166. 6. Cheng J, Valdivia CR, Vaidyanathan R, Balijepalli RC, Ackerman MJ, Makielski JC. Caveolin-3 suppresses late sodium current by inhibiting nNOS-dependent S-nitrosylation of SCN5A. J Mol Cell Cardiol. 2013;61:102–110. 7. Guo J, Wang T, Li X, Shallow H, Yang T, Li W, et al. Cell surface expression of human ether-a-go-go-related gene (hERG) channels is regulated by caveolin-3 protein via the ubiquitin ligase Nedd4-2. J Biol Chem. 2012;287:33132–33141. 8. Vaidyanathan R, Vega AL, Song C, Zhou Q, Tan B, Berger S, et al. The interaction of caveolin 3 protein with the potassium inward rectifier channel Kir2.1: physiology and pathology related to long qt syndrome 9 (LQT9). J Biol Chem. 2013;288:17472–17480. 9. Massaeli H, Sun T, Li X, Shallow H, Wu J, Xu J, et al. Involvement of caveolin in low K+-induced endocytic degradation of cell-surface human ether-a-go-go-related gene (hERG) channels. J Biol Chem. 2010;285:27259–27264. 10. Hedley PL, Kanters JK, Dembic M, Jespersen T, Skibsbye L, Aidt FH, et al. The role of CAV3 in long–QT syndrome: clinical and functional assessment of a caveolin-3/Kv11.1 double heterozygote versus caveolin-3 single heterozygote. Circ Cardiovasc Genet. 2013;6:452–461. 11. Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation. 1999;99:529–533. 12. Shimizu W, Noda T, Takaki H, Kurita T, Nagaya N, Satomi K, et al. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long-QT syndrome. J Am Coll Cardiol. 2003;41:633–642. 13. Nishio Y, Makiyama T, Itoh H, Sakaguchi T, Ohno S, Gong YZ, et al. D85N, a KCNE1 polymorphism, is a disease-causing gene variant in long QT syndrome. J Am Coll Cardiol. 2009;54:812–819. Key Words: Editorials ◼ caveolins ◼ long-QT syndrome ◼ long-QT syndrome 9

Downloaded from http://circgenetics.ahajournals.org/ at MCMASTER UNIV on March 23, 2015

To Be or Not to Be: Long-QT Syndrome Type 9 Michael J Cutler and Elizabeth S. Kaufman Circ Cardiovasc Genet. 2013;6:439-440 doi: 10.1161/CIRCGENETICS.113.000345 Circulation: Cardiovascular Genetics is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2013 American Heart Association, Inc. All rights reserved. Print ISSN: 1942-325X. Online ISSN: 1942-3268

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circgenetics.ahajournals.org/content/6/5/439

Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation: Cardiovascular Genetics can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation: Cardiovascular Genetics is online at: http://circgenetics.ahajournals.org//subscriptions/

Downloaded from http://circgenetics.ahajournals.org/ at MCMASTER UNIV on March 23, 2015

To be or not to be: long-QT syndrome type 9.

To be or not to be: long-QT syndrome type 9. - PDF Download Free
456KB Sizes 0 Downloads 0 Views