A common MLP (muscle LIM protein) variant is associated with cardiomyopathy.
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.
Knöll
Ralph
R
Heart Centre, Georg August University, Götingen, Germany. r.knoell@imperial.ac.uk
Kostin
Sawa
S
Klede
Stefanie
S
Savvatis
Kostas
K
Klinge
Lars
L
Stehle
Ina
I
Gunkel
Sylvia
S
Kötter
Sebastian
S
Babicz
Kamila
K
Sohns
Melanie
M
Miocic
Snjezana
S
Didié
Michael
M
Knöll
Gudrun
G
Zimmermann
Wolfram Hubertus
WH
Thelen
Paul
P
Bickeböller
Heike
H
Maier
Lars S
LS
Schaper
Wolfgang
W
Schaper
Jutta
J
Kraft
Theresia
T
Tschöpe
Carsten
C
Linke
Wolfgang A
WA
Chien
Kenneth R
KR
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
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