Demonstration of a retinitis pigmentosa (RP) phenotype in adult transgenic mice over-expressing the human myoton1c dystrophy protein kinase (DMK)

Purpose: To examine the eyes of transgenic mice over-expressing the DMK transcript and protein products. Eye findings in human DM include pigmentary maculopathy and midperipheral RP like changes.Methods: A transgenic mouse line was generated using a genomic fragment of human DNA containing the DMK gene. Tandem insertion of 50 copies of the transgene was verified using Southern blot analysis. Over-expression of human DMK transcript and protein was demonstrated using Northern and immunoblot analyses, respectively. Enucleated eyes from mice of increasing age up to 12 months along with age matched control littermates were examined histopathologically.Results: Over-expression of human DMK transcript and protein was detected in brain, skeletal muscle, tongue, and eyes of transgenic animals Transgenic skeletal muscle sections revealed diagnostic hallmarks of DM, notably type I fibre atrophy and centronucleation. The eyes of 12 month old transgenic mice revealed complete absence of retinal photo receptors Foci of retinal pigment epithelial cell migration around retinal blood vessels were also detected The 3 month old and control mice had normal appearing retinas.Conclusions: Adult transgenic mice show evidence of an RP phenotype that appears after 3 months of age. This could be due to over-expression of the human DMK gene. Alternativ ely, a host gene essential to photoreceptor survival may have been altered by the transgene. Our findings may be significant in supporting overexpression of the DMK gene product as a mechanism for disease in patients with myotonic dystrophy. Supported by University of Ottawa Medical Research Fund,1 Muscular Dystrophy Association of Canada,2 the Muscular Dystrophy Association (USA),2 and the Medical Research Council of Canada MT-9820.2