Localisation of a gene for dominant cone-rod dystrophy (CORD6) to chromosome 17p
Localisation of a gene for dominant cone-rod dystrophy ( CORD6 ) to chromosome 17pRosemary E.Kelsell, KevinEvans, Cheryl Y.Gregory, Anthony T.Moore1, Alan C.Bird and David M.Hunt*
Department of Molecular Genetics, Institute of Ophthalmology, University College London, Bath Street,London EC1V 9EL,UK and1Department of Ophthalmology, Addenbrooke's Hospital, Hills Road,Cambridge CB2 2QQ,UK
Received December 3, 1996;Revised and Accepted January 21, 1997
We have performed genetic linkage analysis on a four generation British family with cone-rod dystrophy. Significant linkage to the disease gene was obtained with eight marker loci situated on chromosome 17p12-p13. A maximum two-point lod score of 5.93 with no recombination was obtained with marker locusD17S1844. Critical recombinants identified with flanking marker loci placed the disease gene betweenD17S796/D17S938andD17S954, an interval estimated to be 8 cM in size. This new localisation for autosomal dominant cone-rod dystrophy (CORD6) overlaps with regions attributed previously to Leber's congenital amaurosis, central areolar choroidal dystrophy and dominant cone dystrophy. Given their differences in phenotype, the most plausible explanation would be that these different retinal disorders are caused by mutations in different genes mapping close together within the genome.
The chorioretinal dystrophies constitute the largest subgroup of inherited eye disorders which lead to blindness. Cone-rod dystrophy is a severe example of this subgroup, being characterised by the initial loss of visual acuity and colour vision (associated with the degeneration of cone photoreceptor cells), followed by night blindness and peripheral visual field loss (associated with the degeneration of rod photoreceptor cells) (1 ).
Autosomal dominant, X-linked and recessive modes of inheritance have been described and recent genetic studies have implicated nine different genomic loci in the aetiology of cone-rod dystrophy. Autosomal dominant forms of the disorder have been associated with mutations in the peripherin/RDS gene on chromosome 6p21.2-cen (2 ,3 ) and linkage to chromosome 19q13.3-q13.4 has also been reported (4 ,5 ). An X-linked form of the disease has been linked to Xp21.1-p11.3 (6 ). Autosomal recessive forms of cone-rod dystrophy in association with Bardet-Beidl syndrome have been linked, by homozygosity mapping to chromosomes 3, 11q13, 15 and 16q21 (7 -10 ). In addition, two sporadic cases of cone-rod dystrophy have been reported; one in association with a cytogenetically visible deletion of chromosome 18q211-213 (11 ) and the other in association with neurofibromatosis, suggestive of a cone-rod dystrophy gene situated close to theNF1 gene on chromosome 17q11.2 (12 ). Thus, there appear to be a number of genes situated throughout the genome which are involved in the development of the various forms of cone-rod dystrophy.
We undertook a molecular genetic study of a British family with autosomal dominant cone-rod dystrophy. The ophthalmological examination of affected individuals is described in detail elsewhere (K. Evanset al., in preparation). Briefly, the disease in this family displays an early onset, with loss of central vision reported before 7 years of age, progressing to the peripheral visual field later in life. In this report, we present genetic linkage data on this four generation pedigree which establishes a new localisation for cone-rod dystrophy (CORD6) to chromosome 17p12-p13.
A total genome search was undertaken, focusing on previously assigned loci. The two genomic regions already implicated in autosomal dominant cone-rod dystrophy, chromosome 6p21.2-cen containing the peripherin/RDS gene, and chromosome 19q13.3-q13.4, were chosen as the first candidate areas for linkage analysis. These two regions were excluded in our cone-rod dystrophy family (data not shown). Other regions of the genome previously assigned to retinal dystrophy loci were then investigated. It was with marker loci mapping to chromosome 17p that we obtained evidence for linkage in our autosomal dominant cone-rod dystrophy family.
Genotyping was performed with 14 microsatellite marker loci situated on chromosome 17p and the two-point lod scores are presented in Figure1 . Significant linkage was obtained with eight of these marker loci and a maximum lod score of 5.93 ([theta] = 0.00)was obtained withD17S1844.The haplotypes that define the most likely chromosomal interval for the disease-causing gene are indicated in Figure2 . The unaffected individual III-7 and the affected individual III-9 are recombinant forD17S796/D17S938, placing the disease gene centromeric toD17S796/D17S938. The affected individual III-4 is recombinant forD17S954 (as well as the more centromeric marker lociD17S799 andD17S945), placing the cone-rod dystrophy gene telomeric toD17S954. Four of the marker loci that gave a maximum lod score at zero recombination were completely informative in all these recombinant individuals. Therefore, the cone-rod dystrophy gene in this family is flanked by marker lociD17S796/D17S938(two recombination events) andD17S954 (one recombination event), a region estimated to be 8 cM in size (13 ). According to the most recent genetic map of the region, the marker order centromeric fromD17S804 isD17S804-D17S945-D17S1879/D17S1852/D17S954-D17S799 (13 ). However, the recombination events in our family placeD17S945 in a more centromeric position:D17S804-D17S1879/D17S1852-D17S954-D17S799/D17S945. The genetic interval of 8 cM betweenD17S796/D17S938andD17S954 is, therefore, approximate.
We have localised the gene responsible for autosomal dominant cone-rod dystrophy in this study (CORD6), to within an ~8 cM region betweenD17S796/D17S938 andD17S954 on chromosome 17p12-p13. Several other retinal diseases have also been mapped to this region of the genome (see Fig.1 ). Leber's congenital amaurosis, a recessive disease responsible for congenital blindness, maps to withinD17S938 andD17S1353, a 1 cM region situated entirely within the region forCORD6 (14 ,15 ). Central areolar choroidal dystrophy, a dominant progressive disease resulting in visual loss maps to withinD17S5 andD17S520, a 16 cM region which overlaps the 8 cM region assigned forCORD6 (16 ). Finally, two cases of dominant cone dystrophy have been mapped to chromosome 17p (17 ,18 ), the most refined localisation being betweenD17S926/D17S849 andD17S945 (17 ), a 25 cM region that includes the region of theCORD6 gene.
Leber's congenital amaurosis, central areolar choroidal dystrophy, and cone-rod dystrophy are different clinical entities. The progressive loss of the peripheral visual field exhibited in the affected individuals in this cone-rod dystrophy family also clearly distinguishes the phenotype from that of cone dystrophy (K. Evanset al., in preparation). Given their clinical differences, we believe that the most likely explanation is that these different degenerations are caused by mutations within different retinal genes mapping close together within the genome. Such a theory has been postulated before for chromosome 6q, a region associated with several other retinal abnormalities (19 ,20 ).
There are a number of candidate genes for the retinal disorders that map to chromosome 17p, for example, the gene for recoverin,RCV1 (21 ).D17S945 is a microsatellite marker which was isolated from a 50 kb cosmid clone containing the recoverin gene (22 ). In our family, two individuals (III-3 and III-4) were recombinant forD17S945, as well as more telomeric marker loci. Thus, as is indicated by the exclusion data forD17S945 in Figure1 , the recoverin gene is an unlikely candidate for cone-rod dystrophy. Indeed,RCV1 has been similarly ruled out as a candidate for Leber's congenital amaurosis and cone dystrophy mapping to 17p (14 ,17 ,18 ). Recently, mutations have been identified in the human retinal guanylate cyclase gene,GUCD2, in affected members of some Leber's congenital amaurosis families mapping to this region of the genome (23 ). Other candidate genes include [beta]-arrestin 2,ARRB2, the pigment epithelium-derived factor gene,PEDF, and the gene encoding the phosphatidylinositol transfer protein,PITPN (24 ,25 ,26 ). No mutations were detected in thePITPNcoding region in patients with central choroidal areolar dystrophy (16 ) but it remains a candidate gene for other retinal disease genes mapping to 17p, such as the cone-rod dystrophy in this study.
Further refinement of theCORD6 locus is in progress, as well as the screening of candidate genes. The cloning of this disease gene should provide an insight into rod, as well as cone function and aid in our understanding of the pathophysiology of cone-rod dystrophy.
EDTA-blood samples were obtained from 11 affected members, 11 unaffected members and five spouses for linkage analysis. DNA was extracted from these samples with a Nucleon II extraction kit (Scotlab Bioscience). Genotyping was performed with microsatellite marker loci as described previously (20 ). Briefly, 100 ng DNA samples were PCR amplified and labelled by [[alpha]-32P]dCTP incorporation. These amplified products were then separated by denaturing polyacrylamide gel electrophoresis and visualised by autoradiography. Data were collected using LINKSYS 3.1 (27 ), and two-point linkage analysis was performed using the MLINK sub-program of the LINKAGE package 5.10 (28 ). Allele frequencies were calculated from the five spouses in this family as well as an additional seven normal individuals taken from three other families. The cone-rod dystrophy phenotype in this family was analysed as an autosomal dominant trait, with complete penetrance, infantile onset and a frequency of 0.001 for the affected allele.
We thank Dr Marcelle Jay for genealogy work and the Human Genome Mapping Resources Centre for the provision of oligonucleotide primers. This work was supported by the Wellcome Trust (Grant Number 041905) and the TFC Frost Trust.
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