Linkage mapping of autosomal dominant retinitis pigmentosa (RP1) to the pericentric region of human chromosome 8

Abstract

Linkage mapping in a large, seven-generation family with type 2 autosomal dominant retinitis pigmentosa (ADRP) demonstrates linkage between the disease locus (RP1) and DNA markers on the short arm of human chromosome 8. Five markers were most informative for mapping ADRP in this family using two-point linkage analysis. The markers, their maximum lod scores, and recombination distances were ANK1 (ankyrin)—2.0 at 16%; D8S5 (TL11)—5.3 at 17%; D8S87 [a(CA) n repeat]—7.2 at 14%; LPL (lipoprotein lipase)—1.5 at 26%; and PLAT (plasminigen activator, tissue)—10.6 at 7%. Multipoint linkage analysis, using a simplified pedigree structure for the family (which contains 192 individuals and two inbreeding loops), gave a maximum lod score of 12.2 for RP1 at a distance 8.1 cM proximal to PLAT in the pericentric region of the chromosome. Based on linkage data from the CEPH (Paris) reference families and physical mapping information from a somatic cell hybrid panel of chromosome 8 fragments, the most likely order for four of these five loci and the diseases locus is 8pter-LPL-D8S5-D8S87-PLAT-RP1. (The precise location of ANK1 relative to PLAT in this map is not established.) The most likely location for RP1 is in the pericentric region of the chromosome. Recently, several families with ADRP with tight linkage to the rhodopsin locus at 3q21–q24 were reported and a number of specific rhodopsin mutations in families with ADRP have since been reported. In other ADRP families, including the one in this study, linkage to rhodopsin has been excluded. Thus mutations at two different loci, at least, have been shown to cause ADRP. There is no remarkable clinical disparity in the expression of disease caused by these different loci.