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(Investigative Ophthalmology and Visual Science. 2004;45:36-41.)
© 2004 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.03-0787
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Dominant, Gain-of-Function Mutant Produced by Truncation of RPGR

Dong-Hyun Hong, Basil S. Pawlyk, Michael Adamian, and Tiansen Li

From the Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.

PURPOSE. The retinitis pigmentosa GTPase regulator (RPGR) is essential in the maintenance of photoreceptor viability. Mutations in the X-linked RPGR gene have generally been assumed to be recessive. This study was undertaken to investigate whether certain mutant RPGR alleles may act dominantly.

METHODS. An RPGR transgene representing the RPGR ORF15 variant was placed under a non–tissue-specific promoter and introduced into transgenic mice. The transgene was crossed into both a wild type (WT) and an RPGR null background. Its expression was analyzed by RT-PCR, immunoblot analysis, and immunofluorescence. Photoreceptor survival was assessed by electroretinography and histology.

RESULTS. The RPGR transgene transcript underwent photoreceptor-specific, alternative splicing involving the purine-rich region of the ORF15 exon, generating a shortened mRNA and a premature stop codon. This truncation mutant caused more rapid photoreceptor degeneration than that in the RPGR null (knockout) mutant. The disease course was similar, whether the transgene was coexpressed with WT RPGR or expressed alone in the RPGR null background.

CONCLUSIONS. Certain truncated forms of RPGR can behave as a dominant, gain-of-function mutant. These data suggest that human RPGR mutations are not necessarily null and some may also act as dominant alleles, leading to a more severe phenotype than a null mutant.




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