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Lamr1 functional retroposon causes right ventricular dysplasia in mice

Abstract

Arrhythmogenic right ventricular dysplasia (ARVD) is a hereditary cardiomyopathy that causes sudden death in the young. We found a line of mice with inherited right ventricular dysplasia (RVD) caused by a mutation of the gene laminin receptor 1 (Lamr1). This locus contained an intron-processed retroposon that was transcribed in the mice with RVD. Introduction of a mutated Lamr1 gene into normal mice by breeding or by direct injection caused susceptibility to RVD, which was similar to that seen in the RVD mice. An in vitro study of cardiomyocytes expressing the product of mutated Lamr1 showed early cell death accompanied by alteration of the chromatin architecture. We found that heterochromatin protein 1 (HP1) bound specifically to mutant LAMR1. HP1 is a dynamic regulator of heterochromatin sites, suggesting that mutant LAMR1 impairs a crucial process of transcriptional regulation. Indeed, mutant LAMR1 caused specific changes to gene expression in cardiomyocytes, as detected by gene chip analysis. Thus, we concluded that products of the Lamr1 retroposon interact with HP1 to cause degeneration of cardiomyocytes. This mechanism may also contribute to the etiology of human ARVD.

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Figure 1: Massive fibrosis covers the outer side of the right ventricular wall, as with human ARVD, and never extends to the left ventricle.
Figure 2: Location, alignment and expression of Lamr1-tp1.
Figure 3: The expression of Lamr1-tp1 was confirmed only in KK/Rvd heart, liver and skeletal muscle.
Figure 4: The direct gene injections showed the Lamr1-tp1-specific degradation of the myocardium.
Figure 5: Expressional (northern blot) analysis both of the transgenes and native genes in each transgenic mouse model.
Figure 6: Lamr1-tp1 caused cardiomyocyte cell death.
Figure 7: LAMR1-TP1 interacts with HP1-α.

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Acknowledgements

These data were generated through the use of the Celera Discovery System and Celera Genomics' Associated Databases. We thank T. Tanaka and K. Miyake for assistance with DNA sequencing; S. Hirota for histologic expertise; H. Niwa for donating plasmid constructs and providing suggestions; K. Yamamoto for amino-acid sequencing; and H. Kikutani, K. Node and T. Nakagawa for discussions. This work was supported by Grants-in-aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology and from the Ministry of Health and Labor and Welfare, Japan.

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Correspondence to Seiji Takashima or Masafumi Kitakaze.

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Asano, Y., Takashima, S., Asakura, M. et al. Lamr1 functional retroposon causes right ventricular dysplasia in mice. Nat Genet 36, 123–130 (2004). https://doi.org/10.1038/ng1294

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