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Editor—Retinitis pigmentosa (RP) is the term given to a group of inherited retinal degenerations affecting approximately 1 in every 4000 people.1 Clinical presentation includes night blindness, a peripheral bone spicule appearance to the retina, constriction of retinal arterioles, and visual field loss. RP can be inherited in an autosomal dominant, autosomal recessive, or X linked fashion, with autosomal dominant RP (ADRP) accounting for around 20%.2 Within the autosomal dominant category there is both clinical and genetic heterogeneity. Nine ADRP loci have been reported to date. Mutations in rhodopsin account for between 20 and 50% of ADRP3-6 and those in peripherin/RDS for less than 5%,7 8 while around 20% of large families are linked to a major locus on chromosome 19q.9 The remaining six loci, for which genes have not yet been identified, are relatively rare and approximately 15% of families do not map to any known locus, indicating yet further genetic heterogeneity.6 10
The RP1 locus on 8q was first identified by linkage analysis in a large pedigree known as UCLA-RP01, originating in the Appalachian mountains of Kentucky in eastern USA.11The phenotype in UCLA-RP01 is described as type 2 or R type ADRP, with regional and combined loss of both rod and cone photoreceptor sensitivities. A second unrelated family of Australian origin has also been linked to RP1.12 Crossovers in these families place the locus in a 4 cM interval between markers D8S601 and D8S285. The phenotype in both families is reported as showing wide variation in severity and age of onset, and subjects in both were found to carry the gene yet manifest no symptoms. However non-penetrance is rarer at this locus (around 6% in the Kentucky pedigree) than at two other ADRP loci on 7p (RP9 13) and 19q (RP11 9) which have 10% and 35% non-penetrance, respectively.
We now report a new RP1 linked family originating in south west England. The phenotype in this family is similar to that seen in the US and Australian families. Age of onset varies from 12 years to the sixth decade, with simultaneous loss of visual fields and night vision as the first symptoms. Fundus examination in affected subjects shows pale optic discs, peripheral pigment clumping, and attenuated retinal blood vessels. The family includes four subjects under the age of 25 years who are asymptomatic, but who offered DNA samples for linkage analysis to help determine which RP locus was involved in the family. All four subsequently requested to know their results and our interpretation of these, particularly in order to help guide them in career choices. These results were given with supportive counselling, according to predictive test protocols, albeit emphasising the uncertainties of linkage analysis. One of these asymptomatic subjects was found to have inherited the high risk haplotype, but at the age of 16 years showed no detectable abnormality on fundus examination and electrodiagnostic testing (V.7 in fig 1). All members of the family have agreed to publication of the pedigree with linkage results attached.
Microsatellite markers from known ADRP loci were typed in genomic DNA samples from the family by PCR, with incorporation of 32P labelled cytosine, followed by size fractionation on 6% polyacrylamide denaturing gels. For most markers a standard cycling profile of 30-35 cycles at 94°C, 55°C, and 72°C was used, with 20 seconds at each step. Allele frequencies were estimated from panels of between 18 and 34 chromosomes of normal partners of RP patients in this and other UK families. Lod scores were calculated from data files prepared on the LINKSYS (version 3.1) data management package then transferred to the LINKAGE (version 5.1) suite of programs. Linkage analysis was carried out both on a PC and on the Human Genome Mapping Project Resources Centre computing facility.
DNA from the family was tested for linkage to markers from each of the nine known ADRP loci, and crossovers were detected in affected subjects with all but those markers at the RP1 locus at chromosome 8q11. Lod scores for markers from the other ADRP loci are given in table 1. Markers used to establish linkage to theRP1 locus are as follows: 8pter/D8S87/6 cM (including 8cen)/D8S601/3 cM/D8S285/1 cM/D8S166/ 4 cM/D8S507/8qter. This order and genetic distances are approximately as given by Xuet al 12 and agree well with data from the Marshfield integrated human genetic map (http://www.marshmed.org/genetics).
When testing for linkage between the retinal disease in this family andRP1 markers, lod scores were obtained by two different analyses. The first follows the method of Xuet al 12 and assumes full penetrance but excludes all subjects diagnosed unaffected who are under 25 years of age (marked with a question mark in fig 1). Analysis under this model gave maximum two point lod scores of 2.89, 1.09, and 2.66 with markers D8S601, D8S285, and D8S166 against RP respectively, each with no recombination. Multipoint analysis with this model using these three markers gave a maximum lod score of 3.01 at D8S601. The second analysis includes all of the subjects shown but allows for the possibility that apparently normal family members are non-expressing gene carriers. The original report on RP1linkage to chromosome 811 described a pedigree of over 80 affected subjects which included two dead obligate carriers reported to be asymptomatic and a further three living gene carriers with minimal symptoms in their fifties. The second documentedRP1 pedigree12 had two asymptomatic gene carriers out of 11 affected subjects. We therefore assumed a penetrance of approximately 90%. In this way, maximum two point lod scores of 2.76, 1.32, and 2.53 were obtained with these three markers, while the peak multipoint lod score of 2.88 was again at marker D8S601. Haplotypes for the three markers used are shown in fig1. Five other markers from the region were typed in the family but did not add significantly to the results presented.
The pedigree described here does not further refine theRP1 locus, since flanking markers D8S601 and D8S285 detect no crossovers in the family. However, the assignment of a third ADRP family to this locus may imply thatRP1 is among the more common dominant RP loci. Alternatively it is possible that either the Australian or US families are related to this one, given the extensive emigration from the UK (and particularly from the south west) to those countries over the last three centuries. The phenotype in the new family is similar to that described in both of the previously reportedRP1 families. RP1linked pedigrees consistently exhibit wide variation in severity and age of onset of symptoms and include asymptomatic gene carriers, but with a lower frequency of non-penetrance than at theRP9 and RP11 loci. The mechanism of partial penetrance at these loci has not yet been fully elucidated, but McGee et al 14 reported that penetrance of the mutated allele at the 19q RP11 ADRP locus is moderated by the normal allele with which it is paired. The pedigree described here would be consistent with such a mode of inheritance. Sib pair IV.1 and IV.4, who appear to have inherited the same haplotype of markers for chromosome 8 from their normal father, both reported age of onset in their early thirties, while sib pair IV.7 and IV.9, who inherited different versions of chromosome 8 from their father, had onset of symptoms in their mid-thirties and at 12 years of age respectively. Analysis of the other RP1 families may therefore further implicate allelic moderation as a phenomenon common to different forms of RP.
We gratefully acknowledge the Wellcome Trust (grant number 035535/96) and the British Retinitis Pigmentosa Society for funding this research.