title: A common MLP (muscle LIM protein) variant is associated with cardiomyopathy.
abstract: BACKGROUND
  We previously discovered the human 10T-->C (Trp4Arg) missense mutation in exon 2 of the muscle LIM protein (MLP, CSRP3) gene.
  
  
  OBJECTIVE
  We sought to study the effects of this single-nucleotide polymorphism in the in vivo situation.
  
  
  RESULTS
  We now report the generation and detailed analysis of the corresponding Mlp(W4R/+) and Mlp(W4R/W4R) knock-in animals, which develop an age- and gene dosage-dependent hypertrophic cardiomyopathy and heart failure phenotype, characterized by almost complete loss of contractile reserve under catecholamine induced stress. In addition, evidence for skeletal muscle pathology, which might have implications for human mutation carriers, was observed. Importantly, we found significantly reduced MLP mRNA and MLP protein expression levels in hearts of heterozygous and homozygous W4R-MLP knock-in animals. We also detected a weaker in vitro interaction of telethonin with W4R-MLP than with wild-type MLP. These alterations may contribute to an increased nuclear localization of W4R-MLP, which was observed by immunohistochemistry.
  
  
  CONCLUSIONS
  Given the well-known high frequency of this mutation in Caucasians of up to 1%, our data suggest that (W4R-MLP) might contribute significantly to human cardiovascular disease.
authors.affiliation: Heart Centre, Georg August University, Götingen, Germany. r.knoell@imperial.ac.uk
authors.forename: Ralph
authors.initials: R
authors.lastname: Knöll
authors.forename: Sawa
authors.initials: S
authors.lastname: Kostin
authors.forename: Stefanie
authors.initials: S
authors.lastname: Klede
authors.forename: Kostas
authors.initials: K
authors.lastname: Savvatis
authors.forename: Lars
authors.initials: L
authors.lastname: Klinge
authors.forename: Ina
authors.initials: I
authors.lastname: Stehle
authors.forename: Sylvia
authors.initials: S
authors.lastname: Gunkel
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kötter
authors.forename: Kamila
authors.initials: K
authors.lastname: Babicz
authors.forename: Melanie
authors.initials: M
authors.lastname: Sohns
authors.forename: Snjezana
authors.initials: S
authors.lastname: Miocic
authors.forename: Michael
authors.initials: M
authors.lastname: Didié
authors.forename: Gudrun
authors.initials: G
authors.lastname: Knöll
authors.forename: Wolfram Hubertus
authors.initials: WH
authors.lastname: Zimmermann
authors.forename: Paul
authors.initials: P
authors.lastname: Thelen
authors.forename: Heike
authors.initials: H
authors.lastname: Bickeböller
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schaper
authors.forename: Jutta
authors.initials: J
authors.lastname: Schaper
authors.forename: Theresia
authors.initials: T
authors.lastname: Kraft
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Linke
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
mesh_terms: D000367:Age Factors; D000375:Aging; D000818:Animals; D002312:Cardiomyopathy, Hypertrophic / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D064211:Connectin; D004195:Disease Models, Animal; D005355:Fibrosis; D055879:Gene Knock-In Techniques; D005838:Genotype; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006579:Heterozygote; D006720:Homozygote; D060588:LIM Domain Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D016277:Ventricular Function, Left
chemical_list: D064211:Connectin; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C577294:Tcap protein, mouse; C090114:cysteine and glycine-rich protein 3