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Human Molecular Genetics, 2002, Vol. 11, No. 9 993-1003
© 2002 Oxford University Press

Different RPGR exon ORF15 mutations in Canids provide insights into photoreceptor cell degeneration

Qi Zhang1, Gregory M. Acland1, Wen X. Wu2, Jennifer L. Johnson1, Sue Pearce-Kelling1, Brian Tulloch3, Raf Vervoort3,4, Alan F. Wright3 and Gustavo D. Aguirre1,*

1Baker Institute and 2Department of Biomedical Sciences, Cornell University, Ithaca, New York, USA, 3MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK and 4Laboratory for Glycobiology and Developmental Genetics, Center for Human Genetics, University of Leuven, Leuven, Belgium

The canine disease, X-linked progressive retinal atrophy (XLPRA), is similar to human RP3, an X-linked form of retinitis pigmentosa, and maps to the same region in the X chromosome. Analysis of the physical map of the XLPRA and RP3 intervals shows a high degree of conservation in terms of genes and their order. We have found different mutations in exon ORF15 of the RPGR gene in two distinct mutant dog strains (XLPRA1, XLPRA2). Microdeletions resulting in a premature stop or a frameshift mutation result in very different retinal phenotypes, which are allele-specific and consistent for each mutation. The phenotype associated with the frameshift mutation in XLPRA2 is very severe and manifests during retinal development; the phenotype resulting from the XLPRA1 nonsense mutation is expressed only after normal photoreceptor morphogenesis. Splicing of RPGR mRNA transcripts in retina is complex, and either exon ORF15 or exon 19 can be a terminal exon. The retina-predominant transcript contains ORF15 as a terminal exon, and is expressed in normal and mutant retinas. The frameshift mutation dramatically alters the deduced amino acid sequence, and the protein aggregates in the endoplasmic reticulum of transfected cells. The cellular and molecular results in the two canine RPGR exon ORF15 mutations have implications for understanding the phenotypic variability found in human RP3 families that carry similar mutations.

* To whom correspondence should be addressed at: James A. Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA. Tel:+1607 256 5620; Fax: +1607 256 5689; Email: gda1{at}cornell.edu

{dagger} AF385629, AF148800 and AF148798


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