Response by Crotti et al to Letter Regarding Article, “Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3′ Untranslated Region of KCNQ1?”
2016; Lippincott Williams & Wilkins; Volume: 9; Issue: 6 Linguagem: Inglês
10.1161/circgenetics.116.001635
ISSN1942-325X
AutoresLia Crotti, Annukka M. Lahtinen, Carla Spazzolini, Elisa Mastantuono, Maria Cristina Monti, Caterina Morassutto, Gianfranco Parati, Marshall Heradien, Althea Goosen, Peter Lichtner, Thomas Meitinger, Paul A. Brink, Kimmo Kontula, Heikki Swan, Peter J. Schwartz,
Tópico(s)Cardiomyopathy and Myosin Studies
ResumoHomeCirculation: Cardiovascular GeneticsVol. 9, No. 6Response by Crotti et al to Letter Regarding Article, "Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3′ Untranslated Region of KCNQ1?" Free AccessLetterPDF/EPUBAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBResponse by Crotti et al to Letter Regarding Article, "Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3′ Untranslated Region of KCNQ1?" Lia Crotti, MD, PhD Annukka M. Lahtinen, PhD Carla Spazzolini, DVM, MS Elisa Mastantuono, MD Maria Cristina Monti, PhD and Caterina Morassutto, MS Gianfranco Parati, MD Marshall Heradien, MD and Althea Goosen, RN Peter Lichtner, PhD Thomas Meitinger, MD, MSc Paul A. Brink, MD, PhD Kimmo Kontula, MD, PhD Heikki Swan, MD, PhD Peter J. Schwartz, MD Lia CrottiLia Crotti Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy, Department of Molecular Medicine, University of Pavia, Pavia, Italy, Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy Annukka M. LahtinenAnnukka M. Lahtinen Department of Medicine, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland Carla SpazzoliniCarla Spazzolini Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy Elisa MastantuonoElisa Mastantuono Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany Maria Cristina MontiMaria Cristina Monti Department of Public Health, Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia, Italy and Caterina MorassuttoCaterina Morassutto Department of Public Health, Unit of Biostatistics and Clinical Epidemiology, University of Pavia, Pavia, Italy Gianfranco ParatiGianfranco Parati Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital IRCCS Istituto Auxologico Italiano, Milan, Italy, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy Marshall HeradienMarshall Heradien Department of Internal Medicine, University of Stellenbosch, South Africa and Althea GoosenAlthea Goosen Department of Internal Medicine, University of Stellenbosch, South Africa Peter LichtnerPeter Lichtner Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany Thomas MeitingerThomas Meitinger Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany, Institute of Human Genetics, Technische Universität München, Munich, Germany, DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany Paul A. BrinkPaul A. Brink Department of Internal Medicine, University of Stellenbosch, South Africa Kimmo KontulaKimmo Kontula Department of Medicine, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland Heikki SwanHeikki Swan Heart and Lung Center, Helsinki University Central Hospital, Helsinki, Finland Peter J. SchwartzPeter J. Schwartz Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy Originally published1 Dec 2016https://doi.org/10.1161/CIRCGENETICS.116.001635Circulation: Cardiovascular Genetics. 2016;9:581–582In Response:We welcome the opportunity to respond to the expected comments by Amin et al regarding our article on the modifying role of 3′ untranslated region (3′UTR) single-nucleotide polymorphisms (SNPs) in type 1 long-QT syndrome patients.1In the original cohort studied by Amin et al,2 the analysis of 3 small families supported the modifying role of 3′UTR SNPs. Amin et al now propose, as a possible reason for the different results, the predominance of haploinsufficient type 1 long-QT syndrome–causative mutations in our population. However, in our 3 founder families, 2 (KCNQ1 A341V and also KCNQ1 IVS7-2A>G) of the 3 mutations have a dominant-negative effect,3,4 and only 1 (KCNQ1-G589D) reduces the ability of the mutated proteins to form functional tetramers leading to haploinsufficiency.5 This is exactly the same pattern of their 3 families: 2 have a dominant-negative effect (KCNQ1 I235N and 339delF) and 1 is haploinsufficient (KCNQ1 R243C).2 In their 3 families, they observed an effect independently of the property of the mutation, whereas we, with significantly greater sample size, could not replicate their finding in any of our 3 founder families. Furthermore, even when comparing families on the basis of both the functional effect of the mutation and the position (cis versus trans) of the derived allele, we could not confirm the modifying role of 3′UTR SNPs. For example, both our A341V population (n=142 mutation carriers) and Amin et al's 339del F (n=12 mutation carriers) carry mutations with a dominant-negative effect and with the derived allele in trans to the mutation, and our G589D mutation (n=535 mutation carriers) and Amin et al's R243C (n=16 mutation carriers) share haploinsufficiency; however, when compared for the same haplotype combination, they show opposite results.Finally, even though we initially expected to simply validate the findings by Amin et al,2 we did not limit our analysis only to those 3 SNPs. Indeed, our sequencing covered more than half of the KCNQ1 3′UTR sequence, and no other frequently occurring variants (minor allele frequency >1%) were identified in the covered area. According to the Exome Aggregation Consortium (ExAC) Browser,6 there are no other SNPs with minor allele frequency >5% in the KCNQ1 3′UTR; this makes unlikely that any other frequently occurring variants would have a disease-modifying effect in long-QT syndrome.Thus, we stand by our conclusions that what we observed, in a truly large number of type 1 long-QT syndrome subjects, could not support the proposed modifying role of 3′UTR SNPs and that the confounding effect of merging a genetically and clinically heterogeneous group of patients should always be taken into account when studying disease modifiers.Lia Crotti, MD, PhDCenter for Cardiac Arrhythmias of Genetic Origin andLaboratory of Cardiovascular GeneticsIRCCS Istituto Auxologico ItalianoMilan, ItalyDepartment of Molecular MedicineUniversity of PaviaPavia, ItalyDepartment of Cardiovascular, Neural and Metabolic SciencesSan Luca Hospital IRCCS Istituto Auxologico ItalianoMilan, ItalyAnnukka M. Lahtinen, PhDDepartment of MedicineHelsinki University Central HospitalUniversity of HelsinkiHelsinki, FinlandCarla Spazzolini, DVM, MSCenter for Cardiac Arrhythmias of Genetic Origin andLaboratory of Cardiovascular GeneticsIRCCS Istituto Auxologico ItalianoMilan, ItalyElisa Mastantuono, MDInstitute of Human GeneticsHelmholtz Zentrum MünchenNeuherberg, GermanyMaria Cristina Monti, PhDCaterina Morassutto, MSDepartment of Public HealthUnit of Biostatistics and Clinical EpidemiologyUniversity of PaviaPavia, ItalyGianfranco Parati, MDDepartment of Cardiovascular, Neural and Metabolic SciencesSan Luca Hospital IRCCS Istituto Auxologico ItalianoMilan, ItalyDepartment of Medicine and SurgeryUniversity of Milano-BicoccaMilan, ItalyMarshall Heradien, MDAlthea Goosen, RNDepartment of Internal MedicineUniversity of StellenboschSouth AfricaPeter Lichtner, PhDInstitute of Human GeneticsHelmholtz Zentrum MünchenNeuherberg, GermanyThomas Meitinger, MD, MScInstitute of Human GeneticsHelmholtz Zentrum MünchenNeuherberg, GermanyInstitute of Human GeneticsTechnische Universität MünchenMunich, GermanyDZHK (German Centre for Cardiovascular Research), partnersite Munich Heart AllianceMunich, GermanyPaul A. Brink, MD, PhDDepartment of Internal MedicineUniversity of StellenboschSouth AfricaKimmo Kontula, MD, PhDDepartment of MedicineHelsinki University Central HospitalUniversity of HelsinkiHelsinki, FinlandHeikki Swan, MD, PhDHeart and Lung CenterHelsinki University Central HospitalHelsinki, FinlandPeter J. Schwartz, MDCenter for Cardiac Arrhythmias of Genetic Origin andLaboratory of Cardiovascular GeneticsIRCCS Istituto Auxologico ItalianoMilan, ItalyDisclosuresNone.References1. Crotti L, Lahtinen AM, Spazzolini C, Mastantuono E, Monti MC, Morassutto C, et al. Genetic modifiers for the long-QT syndrome: how important is the role of variants in the 3 ′ untranslated region of KCNQ1?Circ Cardiovasc Genet. 2016; 9:330–339. doi: 10.1161/CIRCGENETICS.116.001419.LinkGoogle Scholar2. Amin AS, Giudicessi JR, Tijsen AJ, Spanjaart AM, Reckman YJ, Klemens CA, et al. Variants in the 3 ′ untranslated region of the KCNQ1-encoded Kv7.1 potassium channel modify disease severity in patients with type 1 long QT syndrome in an allele-specific manner.Eur Heart J. 2012; 33:714–723. doi: 10.1093/eurheartj/ehr473.CrossrefMedlineGoogle Scholar3. Brink PA, Crotti L, Corfield V, Goosen A, Durrheim G, Hedley P, et al. Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.Circulation. 2005; 112:2602–2610. doi: 10.1161/CIRCULATIONAHA.105.572453.LinkGoogle Scholar4. Fodstad H, Bendahhou S, Rougier JS, Laitinen-Forsblom PJ, Barhanin J, Abriel H, et al. Molecular characterization of two founder mutations causing long QT syndrome and identification of compound heterozygous patients.Ann Med. 2006; 38:294–304. doi: 10.1080/07853890600756065.CrossrefMedlineGoogle Scholar5. Piippo K, Swan H, Pasternack M, Chapman H, Paavonen K, Viitasalo M, et al. A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics.J Am Coll Cardiol. 2001; 37:562–568.CrossrefMedlineGoogle Scholar6. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al; Exome Aggregation Consortium. Analysis of protein-coding genetic variation in 60,706 humans.Nature. 2016; 536:285–291. doi: 10.1038/nature19057.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByWinbo A, Diamant U, Persson J, Jensen S and Rydberg A (2022) To Modify or Not to Modify: Allele‐Specific Effects of 3'UTR‐KCNQ1 Single Nucleotide Polymorphisms on Clinical Phenotype in a Long QT 1 Founder Population Segregating a Dominant‐Negative Mutation, Journal of the American Heart Association, 11:18, Online publication date: 20-Sep-2022.Cerrone M, Remme C, Tadros R, Bezzina C and Delmar M (2019) Beyond the One Gene–One Disease Paradigm, Circulation, 140:7, (595-610), Online publication date: 13-Aug-2019. Schwartz P, Crotti L and George A (2018) Modifier genes for sudden cardiac death, European Heart Journal, 10.1093/eurheartj/ehy502 Coll M, Pérez-Serra A, Mates J, del Olmo B, Puigmulé M, Fernandez-Falgueras A, Iglesias A, Picó F, Lopez L, Brugada R and Campuzano O (2017) Incomplete Penetrance and Variable Expressivity: Hallmarks in Channelopathies Associated with Sudden Cardiac Death, Biology, 10.3390/biology7010003, 7:1, (3) Kammenga J (2017) The background puzzle: how identical mutations in the same gene lead to different disease symptoms, The FEBS Journal, 10.1111/febs.14080, 284:20, (3362-3373), Online publication date: 1-Oct-2017. Bruce H, Kochunov P, Paciga S, Hyde C, Chen X, Xie Z, Zhang B, Xi H, O'Donnell P, Whelan C, Schubert C, Bellon A, Ament S, Shukla D, Du X, Rowland L, O'Neill H and Hong L (2017) Potassium channel gene associations with joint processing speed and white matter impairments in schizophrenia, Genes, Brain and Behavior, 10.1111/gbb.12372, 16:5, (515-521), Online publication date: 1-Jun-2017. Gnecchi M, Stefanello M and Mura M (2017) Induced pluripotent stem cell technology: Toward the future of cardiac arrhythmias, International Journal of Cardiology, 10.1016/j.ijcard.2017.03.085, 237, (49-52), Online publication date: 1-Jun-2017. Amin A, Pinto Y, Ackerman M and Wilde A (2016) Letter by Amin et al Regarding Article, "Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3′ Untranslated Region of KCNQ1?", Circulation: Cardiovascular Genetics, 9:6, (580-580), Online publication date: 1-Dec-2016. December 2016Vol 9, Issue 6 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIRCGENETICS.116.001635 Originally publishedDecember 1, 2016 PDF download Advertisement SubjectsArrhythmiasGenetic, Association StudiesIon Channels/Membrane TransportSudden Cardiac Death
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