Human Molecular Genetics Advance Access originally published online on January 20, 2005
Human Molecular Genetics 2005 14(5):667-677; doi:10.1093/hmg/ddi063
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Human Molecular Genetics, Vol. 14, No. 5 © Oxford University Press 2005; all rights reserved
A mutation in NFkB interacting protein 1 results in cardiomyopathy and abnormal skin development in wa3 mice
1Genetics Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA, 2Genomics Institute, Wadsworth Center, Albany, NY, USA, 3Department of Molecular Biology and 4Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA, 5Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA, USA, 6Department of Dermatology and Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA and 7Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore CA, USA
* To whom correspondence should be addressed at: Genetics Division BWH, Harvard Medical School New Research Building, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Tel: +1 6175254715; Fax: +1 6175254705; Email: beier{at}receptor.med.harvard.edu
Received December 6, 2004; Revised December 28, 2004; Accepted January 13, 2005
We have identified waved 3 (wa3), a novel recessive mutation that causes abnormalities of the heart and skin. The cardiac defect results in a severe and rapidly progressive dilated cardiomyopathy. We identified the gene mutated in these mice, which we call NFkB interacting protein1 (Nkip1), using positional cloning. Nkip1 is expressed in skin, heart and vascular endothelium and shares homology with a small family of proteins that play a role in the regulation of transcription factors. A C-terminal fragment of this protein was previously identified as the RelA associated inhibitor (RAI). We show that the full-length protein is larger than previously described, and we confirm that it interacts with NFkB in vivo. Expression analysis of genes known to be regulated by NFkB revealed that Intercellular adhesion molecule 1 (Icam1) expression is consistently elevated in mutant mice. This result suggests that wa3 mutant mice represent a potentially important model for the analysis of the role of inflammatory processes in heart disease.