Abstract 8396: A Novel Lamin Interactor (MLIP) is Critical for Cardiac Development and its Potential Role in DCM

A-type lamins have been implicated in the maintenance of cellular commitment and differentiation. Mutations in the LMNA gene are associated with cardiac conduction disease and dilated cardiomyopathy (DCM) in humans. The molecular mechanisms that relate mutations in LMNA with different human diseases are poorly understood and its interactions become of prominence. Using protein:protein interaction assays against Lamin A/C we discovered a novel muscle enriched lamin interacting protein (MLIP) from human heart. MLIP (C6orf142 & 2310046A06rik) is a unique single copy gene that is an innovation of amniotes (reptiles, birds and mammals). The MLIP gene encodes alternatively spliced protein variants (23 to 57kDa) that possess several novel structural motifs not found in other proteins. Like Lamin A/C, MLIP is ubiquitously expressed with tissue specific isoforms found most abundantly in heart, skeletal and smooth muscle. MLIP interacts directly and co-localizes with Lamin A and C in the nuclear envelope. Down-regulation of Lamin A/C expression by shRNA results in the up-regulation and mis-localization of MLIP. In the developing mouse heart MLIP is differentially expressed from E9 to adulthood. Conditional MLIP homozygous null mice die in utero , while hemizygous MLIP null mice develop DCM by 8 weeks of age (Table 1). Ongoing longitudinal studies combining echo with microSPECT-CT will further define the DCM phenotype. In addition to interacting with Lamin, MLIP also binds to genomic DNA within close proximity of genes encoding transcription factors (including Foxc1/c2, Foxa2, Gata4, Mef2c, Pitx2, Rxra and Tbx2) as determined by chromatin immmunoprecipitation and gel mobility shift assays. In conclusion, MLIP is a newly discovered lamin interacting protein that may serve as a tanscriptional regulator that impact genes involved in cardiac development and provides a new direction to study.