Lamr1 functional retroposon causes right ventricular dysplasia in mice.
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.
Asano
Yoshihiro
Y
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 A8 Yamadaoka, Suita, Osaka 565-0871, Japan.
Takashima
Seiji
S
Asakura
Masanori
M
Shintani
Yasunori
Y
Liao
Yulin
Y
Minamino
Tetsuo
T
Asanuma
Hiroshi
H
Sanada
Shoji
S
Kim
Jiyoong
J
Ogai
Akiko
A
Fukushima
Tomi
T
Oikawa
Yumiko
Y
Okazaki
Yasushi
Y
Kaneda
Yasufumi
Y
Sato
Manabu
M
Miyazaki
Jun-ichi
J
Kitamura
Soichiro
S
Tomoike
Hitonobu
H
Kitakaze
Masafumi
M
Hori
Masatsugu
M
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*
D002868:Chromosomal Proteins, Non-Histone; D017474:Receptors, Laminin; D018626:Retroelements; D000090266:Chromobox Protein Homolog 5