title: Tripartite motif-containing 55 identified as functional candidate for spontaneous cardiac hypertrophy in the rat locus cardiac mass 22.
abstract: BACKGROUND
  Left ventricular (LV) hypertrophy is a risk factor for cardiovascular death, but the genetic factors determining LV size and predisposition to hypertrophy are not well understood. We have previously linked the quantitative trait locus cardiac mass 22 (Cm22) on chromosome 2 with cardiac hypertrophy independent of blood pressure in the spontaneously hypertensive rat. From an original cross of spontaneously hypertensive rat with F344 rats, we derived a normotensive polygenic model of spontaneous cardiac hypertrophy, the hypertrophic heart rat (HHR) and its control strain, the normal heart rat (NHR).
  
  
  RESULTS
  To identify the genes and molecular mechanisms underlying spontaneous LV hypertrophy we sequenced the HHR genome with special focus on quantitative trait locus Cm22. For correlative analyses of function, we measured global RNA transcripts in LV of neonatal HHR and NHR and 198 neonatal rats of an HHR × NHR F2 crossbred population. Only one gene within locus Cm22 was differentially expressed in the parental generation: tripartite motif-containing 55 (Trim55), with mRNA downregulation in HHR (P < 0.05) and reduced protein expression. Trim55 mRNA levels were negatively correlated with LV mass in the F2 cross (r = -0.16, P = 0.025). In exon nine of Trim55 in HHR, we found one missense mutation that functionally alters protein structure. This mutation was strongly associated with Trim55 mRNA expression in F2 rats (F = 10.35, P < 0.0001). Similarly, in humans, we found reduced Trim55 expression in hearts of subjects with idiopathic dilated cardiomyopathy.
  
  
  CONCLUSIONS
  Our study suggests that the Trim55 gene, located in Cm22, is a novel candidate gene for polygenic LV hypertrophy independent of blood pressure.
authors.affiliation: aSchool of Applied and Biomedical Sciences, Faculty of Science and Technology, Federation University Australia bHealth and Biomedical Informatics Centre, Melbourne Medical School, University of Melbourne cSchool of Medicine, Deakin University dDepartment of Physiology, University of Melbourne, Victoria, Australia.
authors.forename: Priscilla R
authors.initials: PR
authors.lastname: Prestes
authors.forename: Francine Z
authors.initials: FZ
authors.lastname: Marques
authors.forename: Guillermo
authors.initials: G
authors.lastname: Lopez-Campos
authors.forename: Scott A
authors.initials: SA
authors.lastname: Booth
authors.forename: Maree
authors.initials: M
authors.lastname: McGlynn
authors.forename: Paul
authors.initials: P
authors.lastname: Lewandowski
authors.forename: Lea M D
authors.initials: LM
authors.lastname: Delbridge
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Harrap
authors.forename: Fadi J
authors.initials: FJ
authors.lastname: Charchar
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005838:Genotype; D017379:Hypertrophy, Left Ventricular / Q000235:genetics*; D008297:Male; D040641:Quantitative Trait Loci / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D011918:Rats, Inbred SHR