Aim—X linked retinitis pigmentosa (XLRP) has two genetic loci known as “RP2” and “RP3”. Clinical features reported to diVerentiate RP2 from RP3 include a higher prevalence of myopia and primary cone dysfunction in RP2, and late onset night blindness and tapetal reflex in RP3. Members from 14 XLRP families were examined in an attempt to verify these diVerences. Methods—16 aVected males and 37 females from 14 XLRP families assigned as either RP2 or RP3 by haplotype analysis and/or by heterogeneity analysis were examined. Members of all 14 families who were willing to participate but unavailable for examination were contacted and detailed interviews carried out. Results—No clear phenotypic diVerences were found that could be used to reliably diVerentiate RP2 from RP3 with respect to myopia and onset of night blindness. The tapetal reflex was also found to be present in carriers of both RP2 and RP3. Conclusions—XLRP is a heterogeneous class of rod degenerative disorders with no clear phenotypic diVerentiation between the two genetic loci RP2 and RP3. There is a continuum of clinical presentations which can be seen in both RP2 and RP3, but the features within a given family tend to be consistent. However, interfamilial variability is prevalent leading to a wide range of clinical presentations and more than one abnormal allele at each gene locus cannot be excluded. (Br J Ophthalmol 1999;83:1144–1148) Retinitis pigmentosa (RP) is a well known variably progressive hereditary retinal disorder in which all Mendelian modes of inheritance have been described. 2 It primarily alters rod photoreceptor function as well as aVecting the retinal pigment epithelium. X linked recessive retinitis pigmentosa (XLRP) is genetically and phenotypically heterogeneous for both affected males and carrier females. Two distinct genetic loci have been described and assigned as RP2 (corresponding to the Xp11.2–3 locus) and RP3 (corresponding to the Xp2.1 region). 7 9 10 RP2 and RP3 phenotypes have been distinguished on the basis of tapetal reflex seen in some carrier females in RP3 families, 6 11 12 but there have been no clear distinctions between the two gene loci and clinical presentation. Recently, attempts have been made to correlate phenotypes with genetic locus. Souied and co-workers have previously described two XLRP clinical profiles and recently reported a third “partially dominant” XLRP profile. The first profile shows an earlier onset of myopia in RP2 hemizygotes and the second shows a later onset of night blindness in RP3 hemizygotes. The recently reported third profile shows delayed onset in aVected males with severe expression in carrier females and has been mapped to the RP3 locus. Jacobson and colleagues subsequently reported one family of the RP2 genotype in which the phenotype was initially expressed as a cone photoreceptor dysfunction with subsequent involvement of both rod and cone systems as the disease progressed. Questions have arisen as to whether these reports describe common but unrecognised findings and whether other diVerences exist between the RP2 and RP3 genotypes which have not been recognised. There is currently no widespread agreement as to whether such clinical diVerences exist between the phenotypes produced by the two loci, and the possibility of more than one abnormal allele at each locus has not been excluded. We undertook examination and review of males and females belonging to British XLRP families who had prior genetic studies classifying them as either RP2 or RP3 in an attempt to document phenotypic characteristics and variability. Patients and methods A list of 26 British families with XLRP classified as either RP2 or RP3 by genetic analysis was obtained from the Institute of Ophthalmology in London and the MRC Human Genetics Unit in Edinburgh (Table 1). Heterogeneity analysis as described by Teague et al 4 was carried out at the MRC Human Genetics Unit, Edinburgh, as well as haplotype analysis using genetic markers embracing the region of Xp containing both loci. Briefly, heterogeneity analysis is a method by which data obtained via haplotype analysis is pooled and a statistical estimate of the genotype of the family is obtained. Haplotype analysis was also carried out at the Institute of Ophthalmology, London, on most of the families used in the study. Families for which recombination events clearly positioned the XLRP locus proximal to DX57 (Xp11.3) or between CYBB and DX57 (Xp21.1-p11.3) were classified as RP2 or RP3 accordingly (Hardcastle AJ, unpublished data 1997). The 26 families were contacted and asked to participate in a survey of XLRP, 18 families Br J Ophthalmol 1999;83:1144–1148 1144 Institute of Ophthalmology and Moorfields Eye Hospital, London

AIM X linked retinitis pigmentosa (XLRP) has two genetic loci known as “RP2” and “RP3”. Clinical features reported to differentiate RP2 from RP3 include a higher prevalence of myopia and primary cone dysfunction in RP2, and late onset night blindness and tapetal reflex in RP3. Members from 14 XLRP families were examined in an attempt to verify these differences. METHODS 16 affected males and 37 females from 14 XLRP families assigned as either RP2 or RP3 by haplotype analysis and/or by heterogeneity analysis were examined. Members of all 14 families who were willing to participate but unavailable for examination were contacted and detailed interviews carried out. RESULTS No clear phenotypic differences were found that could be used to reliably differentiate RP2 from RP3 with respect to myopia and onset of night blindness. The tapetal reflex was also found to be present in carriers of both RP2 and RP3. CONCLUSIONS XLRP is a heterogeneous class of rod degenerative disorders with no clear phenotypic differentiation between the two genetic loci RP2 and RP3. There is a continuum of clinical presentations which can be seen in both RP2 and RP3, but the features within a given family tend to be consistent. However, interfamilial variability is prevalent leading to a wide range of clinical presentations and more than one abnormal allele at each gene locus cannot be excluded.

PURPOSE:To evaluate the role of TIMP-1 in inherited retinal degeneration.METHODS:The genomic structure of the TIMP-1 gene was established and male patients with x-linked retinitis pigmentosa 2 from five families were screened for sequence alterations by direct sequencing in all exons, exon-intron boundaries, and the 5' upstream region of the gene.RESULTS:TIMP-1 appears to be expressed in the retina at low levels and consists of six exons spanning a genomic region of approximately 4.5 kb on Xp11.23. No disease-specific sequence alterations were identified. A site substitution in exon 5 was observed in samples from control subjects and patients, but it did not alter the amino acid sequence of the protein product.CONCLUSIONS:The results of this study exclude mutations in the TIMP-1 coding sequence, splice sites, and the 5' upstream region as a cause of retinal degeneration in x-linked retinitis pigmentosa 2. However, an as yet unidentified regulatory element that lies outside these intervals may be implicated. The role of this tightly regulated protein in the normal functioning of the retina has yet to be determined.

Genetic linkage studies have implicated at least two loci for X-linked retinitis pigmentosa (XLRP) on proximal Xp. We now report a defined genetic localization for the RP2 locus to a 5-cM interval in Xp11.3-11.23. Haplotype analysis of polymorphic markers in recombinant individuals from two XLRP families has enabled us to identify DXS8083 and DXS6616 as the new distal and proximal flanking markers for RP2. Using STS-content and YAC end-clone mapping, an approximately 1.2 Mb YAC contig has been established encompassing the proximal RP2 boundary and extending from T1MP1 to DXS1240 in Xp11.23. Several ESTs have been positioned and ordered on this contig, one of which is novel to the region, identified by sequence data-base match to a physically mapped YAC insert terminal STS. Integration of the genetic and physical data has placed four retinally expressed genes proximal to DXS6616, and thereby excluded them from a causitive role in RP2. This work now provides a much needed focus for positional cloning approaches to isolation of the defective gene.