LINKAGE ANALYSIS OF X-LINKED CONE-ROD DYSTROPHY - LOCALIZATION TO XP11.4 AND DEFINITION OF A LOCUS DISTINCT FROM RP2 AND RP3

Progressive X-linked cone-rod dystrophy (COD1) is a retinal disease af fecting primarily the cone photoreceptors. The COD1 locus originally w as localized, by the study of three independent families, to a region between Xp11.3 and Xp21.1, encompassing the retinitis pigmentosa (RP) 3 locus. We have refined the COD1 locus to a limited region of Xp11.4, using two families reported elsewhere and a new extended family. Geno type analysis was performed by use of eight microsatellite markers (te l-M6CA, DXS1068, DXS1058, DXS993, DXS228, DXS1201, DXS1003, and DXS105 5-cent), spanning a distance of 20 cM. Nine-point linkage analysis, by use of the VITESSE program for X-linked disorders, established a maxi mum LOD score (17.5) between markers DXS1058 and DXS993, spanning 4.0 cM. Two additional markers, DXS977 and DXS556, which map between DXS10 58 and DXS993, were used to further narrow the critical region. The RP 3 gene, RPGR, was excluded on the basis of two obligate recombinants, observed in two independent families. In a third family, linkage analy sis did not exclude the RPGR locus. The entire coding region of the RP GR gene from two affected males from family 2 was sequenced and was fo und to be normal. Haplotype analysis of two family branches, containin g three obligate recombinants, two affected and one unaffected, define d the COD1 locus as distal to DXS933 and proximal to DXS556, a distanc e of similar to 1.0 Mb. This study excludes COD1 as an allelic variant of RP3 and establishes a novel locus that is sufficiently defined for positional cloning.