Autosomal dominant retinitis pigmentosa: exclusion of known and mapped genes in three families.

Abstract

Abstract: : Purpose: Three large adRP families, one an African–American family, one of Taiwanese origin, and one of Western European origin, were tested by linkage analysis to determine if their disease was caused by mutations in the known adRP loci. Methods: DNA samples for each family were amplified using florescent labeled primers corresponding to STR markers linked to the 13 known adRP loci. A minimum of two markers was tested for each locus. Labeled PCR product was analyzed on a 3100Avant Genetic Analyzer and allele sizes determined using GeneScan. Linkage analysis was performed using FastLink and GeneHunter. In addition, the proband of each family was further tested by sequencing of the rhodopsin, RDS, RP1 (nt 1472–3216), PRPF31, PRPF8 (nt 1499–1598), HPRP3 (nt 1499–1598), and IMPDH1 loci. Results: The maximum possible lod scores in these three families is 2.3, 4.6 and 2.3, respectively. Linkage testing excluded the known adRP loci as the cause of disease in each of the families, with a lod score of –2 or less between each marker pair. Both the Taiwanese and African–American families exhibit male–to–male disease transmission, excluding the possibility of X–linked inheritance. The family of Western European origin lacks male–to male transmission making it possible that the RP, despite the presence of affected females, is X–linked. This possibility is further substantiated by reports that mutations in ORF15 of RPGR may act in a dominant fashion (Mears et al., AJHG 67:1000–1003). To test this possibility, linkage testing was done using several STRs mapped to the X chromosome. This analysis did not exclude the RP in this family from being X–linked, but testing of ORF15 of RPGR failed to show the presence of a disease–causing mutation. Conclusions: Linkage analysis of three adRP families has failed to link the disease to any of the known adRP loci. These data strongly suggests the presence of additional, unknown adRP genes.

Keywords: mutations • retinal degenerations: hereditary • gene mapping