Mutations in a Protein target of the Pim-1 Kinase Associated with the RP9 Form of Autosomal Dominant Retinitis Pigmentosa

Abstract

Abstract: : Purpose: The purpose of this study was to identify and characterise the gene mutated in the RP9 form of autosomal dominant Retinitis pigmentosa. Methods: Genotyping in a single linked family with polymorphic microsatellite repeats refined the locus to a 2 megabase interval between gs234f24ca1 (embl;G42103) proximally and D7S690 distally. Positional candidate genes were screened by direct sequencing in the linked family and by SSCP analysis in genomic DNA from over 300 RP patients. Results: Two different disease associated mutations were found in a previously unidentified human gene, the mouse orthologue of which has been characterised by its interaction with the Pim-1 oncogene. The gene consists of 6 exons, encoding a 221 amino-acid protein presently named RP9 (previously PAP-1 for Pim-1 associated protein). In the original linked family we identified the missense mutation H137L. A second missense mutation, D170G, was found in a single RP patient. These non-conservative mutations affect amino acid residues conserved in fish, amphibians and mammals and are absent from over 200 control DNA samples. Two other amino-acid polymorphisms were identified, both close to the carboxy-terminus. Conclusion: The finding of these mutations makes it likely that this is the gene mutated in the RP9 form of dominant RP. This gene appears to be expressed in a wide range of tissues but its physiological role/activity is unknown and the precise disease mechanism remains to be determined.

Keywords: 480 mutations • 420 genetics • 385 degenerations/dystrophies