Abstract 14574: MIP1 is a Novel Candidate Gene for Cardiomyopathy and Heart Failure
Introduction: Mutations in genes involved in cardiac mechanosensation (mec), such as the muscle LIM protein (MLP), have been shown to cause cardiomyopathy. Hypothesis: Identification of novel mec genes by searching for new MLP interacting proteins may provide novel insights into underlying mechanisms of heart failure.
Methods and Results: A cardiac specific yeast two hybrid screen identified a novel MLP interacting zinc finger protein (MIP1), located at a chromosomal region recently implicated via different genome-wide association studies in the pathogenesis of dilated cardiomypathy (DCM). The interaction was confirmed by coimmunoprecipitation, colocalization and cross linking experiments. Also MIP1 is stress inducible and chromatin immunoprecipitation experiments revealed that MIP1 binds to the calcineurin promoter and activates NFAT, a known mediator of hypertrophy. MIP1 conditional knockout (cKO) animals failed to adapt to transverse aortic constriction. Four weeks after intervention, fractional shortening (FS) was significantly decreased (46.5±6.3% versus 52.0±3.7%, P<0.04) and LVEDD (3.74±0.19% versus 3.44±0.16%, P<0.003) as well as LVESD (2.00±0.28% versus 1.65±0.14%, P<0.005) were significantly increased in cKO mice (n=10) compared to control littermates (n=8). TUNEL assays, combined with activated caspase, whole gene expression arrays and RT-PCRs strongly suggest that apoptosis is responsible for the observed heart failure phenotype. The reverse experiment, i.e. overexpression of MIP1 in vivo, resulted in marked hypertrophy at the organ and single cell level. Moreover, MIP1 is downregulated in human ischemic cardiomyopathy and DCM (P=0.01). We also sequenced the human MIP1 gene in 916 unrelated DCM patients and identified 4 MIP1 missense mutations (T106M, G179S, A188V, Q531R), 2 of which co-segregate in two small families affected by DCM and arrhythmia. All four variants show abnormalities when analyzed in regards to their ability to interact with MLP, localization, structure, and potential to drive the calcineurin promoter.
Conclusions: MIP1 may be important for the initiation of survival pathways upon biomechanical stress and probably represents a previously unrecognized cardiomyopathy candidate gene.
- © 2012 by American Heart Association, Inc.