CORD9 a new locus for arCRD: Mapping to 8p11, estimation of frequency, evaluation of a candidate gene

PURPOSE. To determine the locus of the mutant gene causing autosomal recess ive cone-rod dystrophy (arCRD) in a consanguineous pedigree, to evaluate a candidate gene expressed in retina that maps to this locus, and to estimate the percentage of arCRD cases caused by mutations in this gene. METHODS. DNAs from family members were genotyped for markers covering the e ntire genome at an average spacing of approximately 9 centimorgans (cM). Th e data were input into a pedigree computer program to produce output files used to calculate lod scores. Significant linkage was revealed at 8cen, pro mpting the genotyping of a number of additional markers. Exons of a candida te gene were sequenced directly by standard fluorescent dideoxy methods. Ha plotype analysis was performed with markers in this locus in 13 multiplex a nd 2 simplex CRD families in which neither parent had disease. RESULTS. Four-point linkage analysis gave a maximum lod score of approximat ely 7.6 at both DSS1769 and GATA101H09 in the large consanguineous family. Recombination events defined an interval of 8.7 cM between D8S1820 and D8S5 32 within which the gene must lie. This 8p11 locus (CORD9) is immediately d istal to but distinct from the RP1 autosomal dominant RP (adRP) locus. Two islands of homozygosity were found in this locus: The alleles of 6 of 10 ma rkers in one of the islands and 2 of 4 in the other were homozygous. The Un iGene cluster Hs.8719 (UniGene System, provided by the National Center for Biotechnology Information and available at http://www.ncbi.nlm.nih.gov/UniG ene), which tags a gene with significant homology to Dual Specificity Phosp hatase 3, maps within the CORD9 interval and is highly expressed in the ret ina. To evaluate this gene as a potential disease candidate, intron-exon st ructure was determined, and exons were screened in the consanguineous famil y. No variants were found that could be related to disease. Haplotype analy sis of 15 other families with CRD, using markers at CORD9, excluded this lo cus in 9 of 15. CONCLUSIONS. A new arCRD locus (CORD9) has been identified corresponding to a yet unidentified gene in the 8.7-cM interval D8S1820-D8S532. No mutation s were found in one candidate gene in affected members of the primary study family. Haplotype analysis of a cohort of 13 multiplex and 2 simplex famil ies with CRD ruled out the CORD9 gene in 9 of 15 of the families. To date, a total of 126 loci carrying gene mutations causing various forms of retina l degeneration have been mapped, and the mutant gene has been identified in 64 of them. However, only 2 loci for arCRD have been documented. This is t he report of a third.