A Novel Recessive Mutation in SPEG Causes Early Onset Dilated Cardiomyopathy
Autoři:
Aviva Levitas aff001; Emad Muhammad aff002; Yuan Zhang aff004; Isaac Perea Gil aff004; Ricardo Serrano aff005; Nashielli Diaz aff004; Maram Arafat aff002; Alexandra A. Gavidia aff004; Michael S. Kapiloff aff005; Mark Mercola aff005; Yoram Etzion aff006; Ruti Parvari aff002; Ioannis Karakikes aff004; Ricardo Serrano aff006; Michael S. Kapiloff aff007; Mark Mercola aff006; Yoram Etzion aff008
Působiště autorů:
Department of Pediatric Cardiology, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
aff001; The Shraga Segal Department of Microbiology, Immunology & Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
aff002; The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel
aff003; Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, California, United States of America
aff004; Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America
aff005; Regenerative Medicine & Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
aff006; Cardiovascular Institute and Department of Medicine, Stanford University, Stanford, CA, USA
aff006; Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
aff007; Cardiovascular Institute and Departments of Ophthalmology and Medicine, Stanford University, Stanford, CA, USA
aff007; Regenerative Medicine & Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel
aff008; Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
aff009
Vyšlo v časopise:
A Novel Recessive Mutation in SPEG Causes Early Onset Dilated Cardiomyopathy. PLoS Genet 16(9): e32767. doi:10.1371/journal.pgen.1009000
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009000
Souhrn
Dilated cardiomyopathy (DCM) is a common cause of heart failure and sudden cardiac death. It has been estimated that up to half of DCM cases are hereditary. Mutations in more than 50 genes, primarily autosomal dominant, have been reported. Although rare, recessive mutations are thought to contribute considerably to DCM, especially in young children. Here we identified a novel recessive mutation in the striated muscle enriched protein kinase (SPEG, p. E1680K) gene in a family with nonsyndromic, early onset DCM. To ascertain the pathogenicity of this mutation, we generated SPEG E1680K homozygous mutant human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) using CRISPR/Cas9-mediated genome editing. Functional studies in mutant iPSC-CMs showed aberrant calcium homeostasis, impaired contractility, and sarcomeric disorganization, recapitulating the hallmarks of DCM. By combining genetic analysis with human iPSCs, genome editing, and functional assays, we identified SPEG E1680K as a novel mutation associated with early onset DCM and provide evidence for its pathogenicity in vitro. Our study provides a conceptual paradigm for establishing genotype-phenotype associations in DCM with autosomal recessive inheritance.
Klíčová slova:
Bone and mineral metabolism – Cardiomyocytes – CRISPR – Gene expression – Homozygosity – Induced pluripotent stem cells – Pathogenesis – Sarcomeres – Human genomics
Zdroje
1. McNally EM, Golbus JR, Puckelwartz MJ. Genetic mutations and mechanisms in dilated cardiomyopathy. J Clin Invest. 2013;123(1):19–26. Epub 2013/01/02. doi: 10.1172/JCI62862 23281406; PubMed Central PMCID: PMC3533274.
2. Towbin JA, Lowe AM, Colan SD, Sleeper LA, Orav EJ, Clunie S, et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. Jama. 2006;296(15):1867–76. doi: 10.1001/jama.296.15.1867 17047217.
3. Watkins H, Ashrafian H, Redwood C. Inherited cardiomyopathies. New England Journal of Medicine. 2011;364(17):1643–56. doi: 10.1056/NEJMra0902923 21524215
4. Dellefave L, McNally EM. The genetics of dilated cardiomyopathy. Curr Opin Cardiol. 2010;25(3):198–204. doi: 10.1097/HCO.0b013e328337ba52 20186049; PubMed Central PMCID: PMC2939233.
5. Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nature reviews Cardiology. 2013;10(9):531. doi: 10.1038/nrcardio.2013.105 23900355
6. Kärkkäinen S, Peuhkurinen K. Genetics of dilated cardiomyopathy. Annals of medicine. 2007;39(2):91–107. doi: 10.1080/07853890601145821 17453673
7. Hershberger RE, Morales A, Siegfried JD. Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals. Genetics in medicine: official journal of the American College of Medical Genetics. 2010;12(11):655–67. doi: 10.1097/GIM.0b013e3181f2481f 20864896; PubMed Central PMCID: PMC3118426.
8. Burkett EL, Hershberger RE. Clinical and genetic issues in familial dilated cardiomyopathy. Journal of the American College of Cardiology. 2005;45(7):969–81. doi: 10.1016/j.jacc.2004.11.066 15808750.
9. Lefeber DJ, de Brouwer AP, Morava E, Riemersma M, Schuurs-Hoeijmakers JH, Absmanner B, et al. Autosomal recessive dilated cardiomyopathy due to DOLK mutations results from abnormal dystroglycan O-mannosylation. PLoS genetics. 2011;7(12):e1002427. doi: 10.1371/journal.pgen.1002427 22242004; PubMed Central PMCID: PMC3248466.
10. Lakdawala NK, Funke BH, Baxter S, Cirino AL, Roberts AE, Judge DP, et al. Genetic testing for dilated cardiomyopathy in clinical practice. Journal of cardiac failure. 2012;18(4):296–303. doi: 10.1016/j.cardfail.2012.01.013 22464770; PubMed Central PMCID: PMC3666099.
11. Pugh TJ, Kelly MA, Gowrisankar S, Hynes E, Seidman MA, Baxter SM, et al. The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing. Genetics in medicine: official journal of the American College of Medical Genetics. 2014;16(8):601–8. doi: 10.1038/gim.2013.204 24503780.
12. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72. doi: 10.1016/j.cell.2007.11.019 18035408.
13. Doudna JA, Charpentier E. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science. 2014;346(6213):1258096. doi: 10.1126/science.1258096 25430774.
14. Matsa E, Burridge PW, Wu JC. Human stem cells for modeling heart disease and for drug discovery. Science translational medicine. 2014;6(239):239ps6. doi: 10.1126/scitranslmed.3008921 24898747; PubMed Central PMCID: PMC4215696.
15. Karakikes I, Ameen M, Termglinchan V, Wu JC. Human induced pluripotent stem cell-derived cardiomyocytes: insights into molecular, cellular, and functional phenotypes. Circulation research. 2015;117(1):80–8. doi: 10.1161/CIRCRESAHA.117.305365 26089365; PubMed Central PMCID: PMC4546707.
16. Seeger T, Shrestha R, Lam CK, Chen C, McKeithan WL, Lau E, et al. A Premature Termination Codon Mutation in MYBPC3 Causes Hypertrophic Cardiomyopathy via Chronic Activation of Nonsense-Mediated Decay. Circulation. 2019;139(6):799–811. doi: 10.1161/CIRCULATIONAHA.118.034624 30586709; PubMed Central PMCID: PMC6443405.
17. Pasqualini FS, Sheehy SP, Agarwal A, Aratyn-Schaus Y, Parker KK. Structural phenotyping of stem cell-derived cardiomyocytes. Stem cell reports. 2015;4(3):340–7. doi: 10.1016/j.stemcr.2015.01.020 25733020; PubMed Central PMCID: PMC4375945.
18. Hayakawa T, Kunihiro T, Dowaki S, Uno H, Matsui E, Uchida M, et al. Noninvasive evaluation of contractile behavior of cardiomyocyte monolayers based on motion vector analysis. Tissue engineering Part C, Methods. 2012;18(1):21–32. doi: 10.1089/ten.TEC.2011.0273 21851323.
19. Mannhardt I, Breckwoldt K, Letuffe-Breniere D, Schaaf S, Schulz H, Neuber C, et al. Human Engineered Heart Tissue: Analysis of Contractile Force. Stem cell reports. 2016;7(1):29–42. doi: 10.1016/j.stemcr.2016.04.011 27211213; PubMed Central PMCID: PMC4944531.
20. Mai CT, Isenburg JL, Canfield MA, Meyer RE, Correa A, Alverson CJ, et al. National population-based estimates for major birth defects, 2010–2014. Birth defects research. 2019;111(18):1420–35. doi: 10.1002/bdr2.1589 31580536; PubMed Central PMCID: PMC7203968.
21. Petrovski S, Gussow AB, Wang Q, Halvorsen M, Han Y, Weir WH, et al. The intolerance of regulatory sequence to genetic variation predicts gene dosage sensitivity. PLoS genetics. 2015;11(9):e1005492. doi: 10.1371/journal.pgen.1005492 26332131
22. Hsieh CM, Fukumoto S, Layne MD, Maemura K, Charles H, Patel A, et al. Striated muscle preferentially expressed genes alpha and beta are two serine/threonine protein kinases derived from the same gene as the aortic preferentially expressed gene-1. The Journal of biological chemistry. 2000;275(47):36966–73. doi: 10.1074/jbc.M006028200 10973969.
23. Liu X, Ramjiganesh T, Chen YH, Chung SW, Hall SR, Schissel SL, et al. Disruption of striated preferentially expressed gene locus leads to dilated cardiomyopathy in mice. Circulation. 2009;119(2):261–8. doi: 10.1161/CIRCULATIONAHA.108.799536 19118250; PubMed Central PMCID: PMC2630246.
24. Hinson JT, Chopra A, Nafissi N, Polacheck WJ, Benson CC, Swist S, et al. HEART DISEASE. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy. Science. 2015;349(6251):982–6. doi: 10.1126/science.aaa5458 26315439; PubMed Central PMCID: PMC4618316.
25. Zaunbrecher RJ, Abel AN, Beussman K, Leonard A, von Frieling-Salewsky M, Fields PA, et al. Cronos Titin Is Expressed in Human Cardiomyocytes and Necessary for Normal Sarcomere Function. Circulation. 2019;140(20):1647–60. doi: 10.1161/CIRCULATIONAHA.119.039521 31587567; PubMed Central PMCID: PMC6911360.
26. Wyles SP, Hrstka SC, Reyes S, Terzic A, Olson TM, Nelson TJ. Pharmacological Modulation of Calcium Homeostasis in Familial Dilated Cardiomyopathy: An In Vitro Analysis From an RBM20 Patient-Derived iPSC Model. Clinical and translational science. 2016;9(3):158–67. doi: 10.1111/cts.12393 27105042; PubMed Central PMCID: PMC4902766.
27. Wyles SP, Li X, Hrstka SC, Reyes S, Oommen S, Beraldi R, et al. Modeling structural and functional deficiencies of RBM20 familial dilated cardiomyopathy using human induced pluripotent stem cells. Human molecular genetics. 2016;25(2):254–65. doi: 10.1093/hmg/ddv468 26604136; PubMed Central PMCID: PMC4706113.
28. Streckfuss-Bomeke K, Tiburcy M, Fomin A, Luo X, Li W, Fischer C, et al. Severe DCM phenotype of patient harboring RBM20 mutation S635A can be modeled by patient-specific induced pluripotent stem cell-derived cardiomyocytes. J Mol Cell Cardiol. 2017;113:9–21. doi: 10.1016/j.yjmcc.2017.09.008 28941705.
29. MacLennan DH, Kranias EG. Phospholamban: a crucial regulator of cardiac contractility. Nature reviews Molecular cell biology. 2003;4(7):566–77. doi: 10.1038/nrm1151 12838339.
30. Quick AP, Wang Q, Philippen LE, Barreto-Torres G, Chiang DY, Beavers D, et al. SPEG (Striated Muscle Preferentially Expressed Protein Kinase) Is Essential for Cardiac Function by Regulating Junctional Membrane Complex Activity. Circulation research. 2017;120(1):110–9. doi: 10.1161/CIRCRESAHA.116.309977 27729468; PubMed Central PMCID: PMC5218854.
31. Agrawal PB, Pierson CR, Joshi M, Liu X, Ravenscroft G, Moghadaszadeh B, et al. SPEG interacts with myotubularin, and its deficiency causes centronuclear myopathy with dilated cardiomyopathy. American journal of human genetics. 2014;95(2):218–26. doi: 10.1016/j.ajhg.2014.07.004 25087613; PubMed Central PMCID: PMC4129406.
32. Qualls AE, Donkervoort S, Herkert JC, D'Gama A M, Bharucha-Goebel D, Collins J, et al. Novel SPEG mutations in congenital myopathies: Genotype-phenotype correlations. Muscle & nerve. 2019;59(3):357–62. doi: 10.1002/mus.26378 30412272.
33. Liu X, Hall SRR, Wang Z, Huang H, Ghanta S, Di Sante M, et al. Rescue of neonatal cardiac dysfunction in mice by administration of cardiac progenitor cells in utero. Nature communications. 2015;6:8825. doi: 10.1038/ncomms9825 26593099; PubMed Central PMCID: PMC4673493.
34. Quan C, Li M, Du Q, Chen Q, Wang H, Campbell D, et al. SPEG Controls Calcium Reuptake Into the Sarcoplasmic Reticulum Through Regulating SERCA2a by Its Second Kinase-Domain. Circulation research. 2019;124(5):712–26. doi: 10.1161/CIRCRESAHA.118.313916 30566039.
35. Davis J, Davis LC, Correll RN, Makarewich CA, Schwanekamp JA, Moussavi-Harami F, et al. A Tension-Based Model Distinguishes Hypertrophic versus Dilated Cardiomyopathy. Cell. 2016;165(5):1147–59. doi: 10.1016/j.cell.2016.04.002 27114035; PubMed Central PMCID: PMC4874838.
36. Du CK, Morimoto S, Nishii K, Minakami R, Ohta M, Tadano N, et al. Knock-in mouse model of dilated cardiomyopathy caused by troponin mutation. Circulation research. 2007;101(2):185–94. doi: 10.1161/CIRCRESAHA.106.146670 17556660.
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