International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)

Table of Contents * Complex Genetics * Developmental Genetics * Gene Annotation * Gene Discovery * Genome Sequencing * Functional Genomics * Mutagenesis * Presentations * Verne Chapman Memorial Lecture

A MUTATION IN P53 BINDING PROTEIN RELATED PROTEIN CAUSES DILATED CARDIOMYOPATHY AND SKIN DEFECTS IN WA3 MICE

Bruce Herron
Harvard Medical School
Division of Genetics
Brigham & Womens Hospital
75 Francis Street
Boston MA 02115-6110, USA

Co-Authors: 1) Rao C, 1) Pacella L, 1) Semsarian C, 1) Seidman C, 3) Stubbs L, 2) Millar S, 1) Beier DR
Institutions: 1) Brigham and Women's Hospital, Harvard Medical School, 2) Dept of Dermatology, University of Pennsylvania, 3) Human Genome Center, Lawrence Livermore National Laboratory

We have previously described a spontaneous mutation that affects the development of skin and heart in mice called waved 3(wa3). While wa3 is similar to wa1 and wa2 mice, it also includes a perinatal onset cardiomyopathy with regions of cardiomyocyte necrosis. This disorder progresses with age, resulting in transmural ventricular fibrosis and dilated cardiomyopathy.

We have identified a mutation in a partially characterized gene previously called RAI. Comparative sequencing has revealed a 15 base pair deletion in wa3 mice that removes a splice donor site. This mutation results in a truncation of the translated gene product.

Characterization of this gene uncovered additional 5' sequences. Database analysis indicates it is most similar to P53 binding protein 2, a gene previously shown to interact with P53, Bcl-2, and NFkB. In-situ analysis has indicated that this gene is expressed in epidermal cell types. Cardiovascular expression was also detected in the atria, ventricles, and in the arterial endothelial cells.

We propose that a loss of function mutation in 53bprp results in abnormal epidermal cell growth. This results in open eyes at birth and may contribute to the hair phenotype. Furthermore, the focal regions of cardiac necrosis seen in these mice are consistent with an ischemic injury. Abnormalities in endothelial cell growth in coronary arteries may result in ischemia, leading to cardiomyocyte death.