Knock-out of nexilin in mice leads to dilated cardiomyopathy and endomyocardial fibroelastosis
- 831 Downloads
Cardiomyopathy is one of the most common causes of chronic heart failure worldwide. Mutations in the gene encoding nexilin (NEXN) occur in patients with both hypertrophic and dilated cardiomyopathy (DCM); however, little is known about the pathophysiological mechanisms and relevance of NEXN to these disorders. Here, we evaluated the functional role of NEXN using a constitutive Nexn knock-out (KO) mouse model. Heterozygous (Het) mice were inter-crossed to produce wild-type (WT), Het, and homozygous KO mice. At birth, 32, 46, and 22 % of the mice were WT, Het, and KO, respectively, which is close to the expected Mendelian ratio. After postnatal day 6, the survival of the Nexn KO mice decreased dramatically and all of the animals died by day 8. Phenotypic characterizations of the WT and KO mice were performed at postnatal days 1, 2, 4, and 6. At birth, the relative heart weights of the WT and KO mice were similar; however, at day 4, the relative heart weight of the KO group was 2.3-fold higher than of the WT group. In addition, the KO mice developed rapidly progressive cardiomyopathy with left ventricular dilation and wall thinning and decreased cardiac function. At day 6, the KO mice developed a fulminant DCM phenotype characterized by dilated ventricular chambers and systolic dysfunction. At this stage, collagen deposits and some elastin deposits were observed within the left ventricle cavity, which resembles the features of endomyocardial fibroelastosis (EFE). Overall, these results further emphasize the role of NEXN in DCM and suggest a novel role in EFE.
KeywordsDilated cardiomyopathy Heart failure Endocardial fibroelastosis Nexilin Knock-out mice
We would like to thank Sandra Wrobel, Annett Liebers and Maren Behrensen for their technical support.
Compliance with ethical standards
The generation and characterization of the Nexn KO mice was supported by grants from the Bundesministerium für Bildung und Forschung, NGFN and NGFN-plus and Infrafrontier grant (01KX1012) as well as from the DZHK (German Centre for Cardiovascular Research) and the German Ministry of Research and Education (BMBF). Furthermore the project was also supported by the Leducq Foundation (Research grant Nr. 11, CVD 04) and the Association Institut de Myologie (Paris). Current funding is provided by the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed and sysINFLAME), the FP7 European Union project CVgenes@target (261123) and a grant from the Fondation Leducq (CADgenomics: Understanding Coronary Artery Disease Genes, 12CVD02. Further grants were received by the local focus program “Medizinische Genetik” of the Universität zu Lübeck. This study was also supported through the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence ‘Inflammation at Interfaces’.
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest
- 1.Aherrahrou Z, Doehring LC, Kaczmarek PM, Liptau H, Ehlers EM, Pomarino A, Wrobel S, Gotz A, Mayer B, Erdmann J, Schunkert H (2007) Ultrafine mapping of Dyscalc1 to an 80-kb chromosomal segment on chromosome 7 in mice susceptible for dystrophic calcification. Physiol Genomics 28:203–212. doi: 10.1152/physiolgenomics.00133.2006 PubMedCrossRefGoogle Scholar
- 4.Colan SD, Lipshultz SE, Lowe AM, Sleeper LA, Messere J, Cox GF, Lurie PR, Orav EJ, Towbin JA (2007) Epidemiology and cause-specific outcome of hypertrophic cardiomyopathy in children: findings from the Pediatric Cardiomyopathy Registry. Circulation 115:773–781. doi: 10.1161/CIRCULATIONAHA.106.621185 PubMedCrossRefGoogle Scholar
- 5.Cotran RS, Kumar V, Fausto N, Nelso F, Robbins SL, Abbas AK (2005). In: Robbins and Cotran (ed) Pathologic basis of disease, 8th edn. Saunders Elsevier, St. Louis, p 607Google Scholar
- 8.Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, Dubourg O, Kuhl U, Maisch B, McKenna WJ, Monserrat L, Pankuweit S, Rapezzi C, Seferovic P, Tavazzi L, Keren A (2008) Classification of the cardiomyopathies: a position statement from the European Society Of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 29:270–276. doi: 10.1093/eurheartj/ehm342 PubMedCrossRefGoogle Scholar
- 9.Ervasti JM (2000) Structure and function of the dystrophin-glycoprotein complex. madame curie bioscience database (Internet). Landes Bioscience, AustinGoogle Scholar
- 14.Haas J, Frese KS, Peil B, Kloos W, Keller A, Nietsch R, Feng Z, Muller S, Kayvanpour E, Vogel B, Sedaghat-Hamedani F, Lim WK, Zhao X, Fradkin D, Kohler D, Fischer S, Franke J, Marquart S, Barb I, Li DT, Amr A, Ehlermann P, Mereles D, Weis T, Hassel S, Kremer A, King V, Wirsz E, Isnard R, Komajda M, Serio A, Grasso M, Syrris P, Wicks E, Plagnol V, Lopes L, Gadgaard T, Eiskjaer H, Jorgensen M, Garcia-Giustiniani D, Ortiz-Genga M, Crespo-Leiro MG, Deprez RH, Christiaans I, van Rijsingen IA, Wilde AA, Waldenstrom A, Bolognesi M, Bellazzi R, Morner S, Bermejo JL, Monserrat L, Villard E, Mogensen J, Pinto YM, Charron P, Elliott P, Arbustini E, Katus HA, Meder B (2014) Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J. doi: 10.1093/eurheartj/ehu301 Google Scholar
- 15.Hassel D, Dahme T, Erdmann J, Meder B, Huge A, Stoll M, Just S, Hess A, Ehlermann P, Weichenhan D, Grimmler M, Liptau H, Hetzer R, Regitz-Zagrosek V, Fischer C, Nurnberg P, Schunkert H, Katus HA, Rottbauer W (2009) Nexilin mutations destabilize cardiac Z-disks and lead to dilated cardiomyopathy. Nat Med 15:1281–1288. doi: 10.1038/nm.2037 PubMedCrossRefGoogle Scholar
- 16.Hershberger RE, Norton N, Morales A, Li D, Siegfried JD, Gonzalez-Quintana J (2010) Coding sequence rare variants identified in MYBPC3, MYH6, TPM1, TNNC1, and TNNI3 from 312 patients with familial or idiopathic dilated cardiomyopathy. Circ Genetics 3:155–161. doi: 10.1161/CIRCGENETICS.109.912345 Google Scholar
- 18.Jiao M, Han L, Wang HL, Jin M, Wang XF, Zheng K, Liang YM, Xiao YY (2010) [A long-term follow-up study on the clinical treatment of 75 cases with primary endocardial fibroelastosis]. Zhonghua er ke za zhi. Chin J Pediatr 48:603–609Google Scholar
- 20.Kamisago M, Schmitt JP, McNamara D, Seidman C, Seidman JG (2006) Sarcomere protein gene mutations and inherited heart disease: a beta-cardiac myosin heavy chain mutation causing endocardial fibroelastosis and heart failure. Novart Fdn Symp 274:176–189. doi: 10.1002/0470029331.ch11 (discussion 189–195, 272–176)CrossRefGoogle Scholar
- 21.Kaufman MH, Bard JBL (1999) The anatomical basis of mouse development. Academic Press Kaufman, LondonGoogle Scholar
- 23.Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB, American Heart A, Council on Clinical Cardiology HF, Transplantation C, Quality of C, Outcomes R, Functional G, Translational Biology Interdisciplinary Working G, Council on E, Prevention (2006) Contemporary definitions and classification of the cardiomyopathies: an American Heart association scientific statement from the council on clinical cardiology, heart failure and transplantation committee; quality of care and outcomes research and functional genomics and translational biology interdisciplinary working groups; and council on epidemiology and prevention. Circulation 113:1807–1816. doi: 10.1161/CIRCULATIONAHA.106.174287 PubMedCrossRefGoogle Scholar
- 27.Poppe TT, Ferguson HW (2006) Cardiovascular system. In systemic pathology of fish. Scotian Press, LondonGoogle Scholar
- 29.Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, O’Connell J, Olsen E, Thiene G, Goodwin J, Gyarfas I, Martin I, Nordet P (1996) Report of the 1995 World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Circulation 93:841–842PubMedCrossRefGoogle Scholar