RNAseq reveals mechanisms of cardiomyopathy in Mlp-C58G knock-in mice: SI:Abstracts ISHR-ES Amsterdam

M. Ehsan, M. Kelly, C. Hooper, J. Beglov, B. Davies, K. Fleischanderld, E. Ehler, C. Redwood, H. Watkins, K. Gehmlich

Research output: Contribution to journalMeeting abstract


Background: Hypertrophic cardiomyopathy (HCM) is a common inherited genetic disorder. Mutations in the gene Cysteine-and Glycine Rich Protein 3, CSRP3, encoding for the protein Muscle Lim Protein (MLP) have been shown to cause HCM and dilated cardiomyopathy (DCM). In contrast to other HCM causing gene, MLP is non-sarcomeric and has important role in signaling within cardiomyocytes. Linkage analysis in a large German family led to identification of C58G missense mutation in CSRP3 as HCM causing.

Methods and results: To better understand the underlying pathogenesis of HCM caused by this mutation knock-in (KI) mouse model was generated. Cardiac function of heterozygous (KI/+) and homozygous (KI/KI) was assessed by echocardiography and invasive haemodynamic measurements. Underlying hypertrophy and heart failure signaling pathways were assessed in tissue harvested from these animals. KI/+ mice were unremarkable from the wild type littermates. KI/KI mice presented with characteristics of dilated cardiomyopathy with compensatory hypertrophy, such as significantly diminished ejection fraction and fractional shortening. At the molecular level, RNAseq and qPCR results both highlighted induction of markers of heart failure and hypertrophy. Key genes such as Acta1, Myh7, Tgfb, Nppa, Nppb, Ankrd1/2 were all upregulated. Findings from KEGG pathways and GOrilla analysis supported the phenotype. Total MLP protein was reduced in both KI/+ (by 50%) and KI/KI (by 80%) and both invitro and in vivo showed that the reduction in protein is caused by increased activity of the ubiquitin proteasomal system.

Conclusion: MLP mouse model represents a novel model to recapitulate and study pathological molecular signaling in cardiomyopathies caused by mutations non-sarcomeric genes.
Original languageEnglish
JournalJournal of Molecular and Cellular Cardiology
Early online date4 Aug 2018
Publication statusPublished - 2018


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