title: 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.
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 A8 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Asano
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Masanori
authors.initials: M
authors.lastname: Asakura
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Shintani
authors.forename: Yulin
authors.initials: Y
authors.lastname: Liao
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Minamino
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.forename: Shoji
authors.initials: S
authors.lastname: Sanada
authors.forename: Jiyoong
authors.initials: J
authors.lastname: Kim
authors.forename: Akiko
authors.initials: A
authors.lastname: Ogai
authors.forename: Tomi
authors.initials: T
authors.lastname: Fukushima
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Oikawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
authors.forename: Manabu
authors.initials: M
authors.lastname: Sato
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Miyazaki
authors.forename: Soichiro
authors.initials: S
authors.lastname: Kitamura
authors.forename: Hitonobu
authors.initials: H
authors.lastname: Tomoike
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
mesh_terms: D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000209:etiology / Q000235:genetics*; D019556:COS Cells; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017474:Receptors, Laminin / Q000235:genetics* / Q000378:metabolism; D018626:Retroelements / Q000502:physiology*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D017474:Receptors, Laminin; D018626:Retroelements; D000090266:Chromobox Protein Homolog 5