Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is a frequent genetic cardiac disease and the most common cause of sudden cardiac death in young individuals. Most of the currently known HCM disease genes encode sarcomeric proteins. Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations. We used linkage analysis and identified a CSRP3 missense mutation in a large German family affected by HCM. We confirmed CSRP3 as an HCM disease gene. Furthermore, CSRP3 missense mutations segregating with HCM were identified in four other families. We used a newly designed monoclonal antibody to show that muscle LIM protein (MLP), the protein encoded by CSRP3, is mainly a cytosolic component of cardiomyocytes and not tightly anchored to sarcomeric structures. Our functional data from both in vitro and in vivo analyses suggest that at least one of MLP's mutated forms seems to be destabilized in the heart of HCM patients harbouring a CSRP3 missense mutation. We also present evidence for mild skeletal muscle disease in affected persons. Our results support the view that HCM is not exclusively a sarcomeric disease and also suggest that impaired mechano-sensory stress signalling might be involved in the pathogenesis of HCM.
Geier
Christian
C
Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Med. Klinik m. S. Kardiologie, 13353 Berlin, Germany. christian.geier@charite.de
Gehmlich
Katja
K
Ehler
Elisabeth
E
Hassfeld
Sabine
S
Perrot
Andreas
A
Hayess
Katrin
K
Cardim
Nuno
N
Wenzel
Katrin
K
Erdmann
Bettina
B
Krackhardt
Florian
F
Posch
Maximilian G
MG
Osterziel
Karl J
KJ
Bublak
Angelika
A
Nägele
Herbert
H
Scheffold
Thomas
T
Dietz
Rainer
R
Chien
Kenneth R
KR
Spuler
Simone
S
Fürst
Dieter O
DO
Nürnberg
Peter
P
Ozcelik
Cemil
C
D000818:Animals; D019556:COS Cells; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D060588:LIM Domain Proteins; D008297:Male; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010375:Pedigree; D012518:Sarcomeres / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics
D060588:LIM Domain Proteins; D009124:Muscle Proteins; C090114:cysteine and glycine-rich protein 3