Form Of Retinal Dystrophy Research Articles

Ayurvedic management of Retinitis Pigmentosa (Doshandha) - A Case Study

Retinitis pigmentosa (RP) is an inherited, degenerative eye disease that causes severe vision impairment due to the progressive degeneration of rod photoreceptor cells in retina. This form of retinal dystrophy manifests initial symptoms independentof age; thus, RP diagnosis occurs anywhere from early infancy to late adulthood. This primary pigmentary retinal dystrophy is a hereditary disorder predominantly affecting the rods more than the cones. The main classical triads of retinitis pigmentosa are arteriolar attenuation, Retinal bone spicule pigmentation and Waxy disc pallor. The main treatment of retinitis pigmentosa is by using Low vision aids (LVA) and Genetic counseling. As such a complete cure for retinitis pigmentosa is not present. So a treatment protocol has to be adopted that helps in at least the symptomatic relief. In Ayurveda, the signs and symptoms of this can be compared with the Lakshanas of Doshandha which is one among the Dristigata Roga. It is considered as a diseased condition in which sunset will obliterate the Dristi Mandala and makes the person blind at night time. During morning hours the rising sunrays will disperse the accumulated Dosas from Dristi to clear vision. This disease resembles Kaphajatimira in its pathogenesis, but the night blindness is the special feature. Since the disease is purely Kaphaja, a treatment attempt is planned in Kaphara and Brimhana line. The present paper discusses a case of retinitis pigmentosa and it’s Ayurvedic Treatment.

Gene panel sequencing in Brazilian patients with retinitis pigmentosa

BackgroundRetinal dystrophies constitute a group of diseases characterized by clinical variability and pronounced genetic heterogeneity. Retinitis pigmentosa is the most common subtype of hereditary retinal dystrophy and is characterized by a progressive loss of peripheral field vision (Tunnel Vision), eventual loss of central vision, and progressive night blindness. The characteristics of the fundus changes include bone-spicule formations, attenuated blood vessels, reduced and/or abnormal electroretinograms, changes in structure imaged by optical coherence tomography, and subjective changes in visual function. The different syndromic and nonsyndromic forms of retinal dystrophies can be attributed to mutations in more than 250 genes. Molecular diagnosis for patients with retinitis pigmentosa has been hampered by extreme genetic and clinical heterogeneity between retinitis pigmentosa and other forms of retinal dystrophies. Next generation sequencing (NGS) technologies are among the most promising techniques to identify pathogenic variations in retinal dystrophies.PurposeThe purpose of this study was to discover the molecular diagnosis for Brazilian patients clinically diagnosed with a retinitis pigmentosa pattern of inheritance by using NGS technologies.Materials and methodsSixteen patients with the clinical diagnosis of retinitis pigmentosa were included in the study. Their DNA was sequenced in a panel with 132 genes related to retinal dystrophies using the Illumina® platform. Sequence analysis and variation calling was performed using Soft Genetics®, NextGene, and Geneticist Assistant software. The criteria for pathogenicity analysis were established according to the results of prediction programs (Polyphen 2, Mutation taster and MetaCore™) and comparison of pathogenic variations found with databases.ResultsThe identified potentially pathogenic variations were all confirmed by Sanger sequencing. There were 89 variations predicted as pathogenic, but only 10 of them supported the conclusion of the molecular diagnosis. Five of the nine patients were autosomal dominant RP (56%), two (22%) were autosomal recessive RP, and two (22%) were X-linked RP. Nine of the 16 patients (56%) had probably positive or positive results.ConclusionThe Next Generation Sequencing used in this study allowed the molecular diagnosis to be confirmed in 56% of the patients and clarified the inheritance pattern of the patient’s retinal dystrophies.

Molecular genetics of Leber congenital amaurosis in Chinese: New data from 66 probands and mutation overview of 159 probands

Leber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophy. We have previously performed a mutational analysis of the known LCA-associated genes in probands with LCA by both Sanger and whole exome sequencing. In this study, whole exome sequencing was carried out on 66 new probabds with LCA. In conjunction with these data, the present study provides a comprehensive analysis of the spectrum and frequency of all known genes associated with retinal dystrophy in a total of 159 Chinese probands with LCA. The known genes responsible for all forms hereditary retinal dystrophy were included based on information from RetNet. The candidate variants were filtered by bioinformatics analysis and confirmed by Sanger sequencing. Potentially causative mutations were further validated in available family members. Overall, a total of 118 putative pathogenic mutations from 23 genes were identified in 56.6% (90/159) of probands. These mutations were harbored in 13 LCA-associated genes and in ten genes related to other forms of retinal dystrophy. The most frequently mutated gene in probands with LCA was GUCY2D (10.7%, 17/159). A series of mutational analyses suggests that all known genes associated with retinal dystrophy account for 56.6% of Chinese patients with LCA. A comprehensive molecular genetic analysis of Chinese patients with LCA provides an overview of the spectrum and frequency of ethno-specific mutations of all known genes, as well as indications about other unknown genes in the remaining probands who lacked identified mutations.

Next generation sequencing based identification of disease-associated mutations in Swiss patients with retinal dystrophies.

Inherited monogenic diseases of the retina and vitreous affect approximately 1 in 2000 individuals. They are characterized by tremendous genetic heterogeneity and clinical variability involving mutations in approximately 250 genes and more than 20 different clinical phenotypes. Clinical manifestations of retinal dystrophies (RDs) range from mild retinal dysfunctions to severe congenital forms of blindness. A detailed clinical diagnosis and the identification of causative mutations are crucial for genetic counseling of affected patients and their families, for understanding genotype-phenotype correlations and developing therapeutic approaches. Using whole exome sequencing (WES) we have established a reliable and efficient high-throughput analysis pipeline to identify disease-causing mutations. Our data indicate that this approach enables us to genetically diagnose approximately 64% of the patients (n = 58) with variant(s) in known disease-associated genes. We report 20 novel and 26 recurrent variants in genes associated with RDs. We also identified a novel phenotype for mutations in C2orf71 and provide functional evidence for exon skipping due to a splice-site variant identified in FLVCR1. In conclusion, WES can rapidly identify variants in various families affected with different forms of RDs. Our study also expands the clinical and allelic spectrum of genes associated with RDs in the Swiss population.

Application of Whole Exome Sequencing in Six Families with an Initial Diagnosis of Autosomal Dominant Retinitis Pigmentosa: Lessons Learned

This study aimed to identify the genetics underlying dominant forms of inherited retinal dystrophies using whole exome sequencing (WES) in six families extensively screened for known mutations or genes. Thirty-eight individuals were subjected to WES. Causative variants were searched among single nucleotide variants (SNVs) and insertion/deletion variants (indels) and whenever no potential candidate emerged, copy number variant (CNV) analysis was performed. Variants or regions harboring a candidate variant were prioritized and segregation of the variant with the disease was further assessed using Sanger sequencing in case of SNVs and indels, and quantitative PCR (qPCR) for CNVs. SNV and indel analysis led to the identification of a previously reported mutation in PRPH2. Two additional mutations linked to different forms of retinal dystrophies were identified in two families: a known frameshift deletion in RPGR, a gene responsible for X-linked retinitis pigmentosa and p.Ser163Arg in C1QTNF5 associated with Late-Onset Retinal Degeneration. A novel heterozygous deletion spanning the entire region of PRPF31 was also identified in the affected members of a fourth family, which was confirmed with qPCR. This study allowed the identification of the genetic cause of the retinal dystrophy and the establishment of a correct diagnosis in four families, including a large heterozygous deletion in PRPF31, typically considered one of the pitfalls of this method. Since all findings in this study are restricted to known genes, we propose that targeted sequencing using gene-panel is an optimal first approach for the genetic screening and that once known genetic causes are ruled out, WES might be used to uncover new genes involved in inherited retinal dystrophies.

Novel homozygous large deletion including the 5' part of the SPATA7 gene in a consanguineous Israeli Muslim Arab family.

To identify the genetic defect in a consanguineous Israeli Muslim Arab family with juvenile retinitis pigmentosa (RP). DNA samples were collected from the index patient, her parents, her affected sister, and two non-affected siblings. Genome-wide linkage analysis with 250K single nucleotide polymorphism (SNP) arrays was performed using DNA from the two affected patients. Owing to consanguinity in the family, we applied homozygosity mapping to identify the disease-causing gene. The candidate gene SPATA7 was screened for mutations with PCR amplifications and direct Sanger sequencing. Following high-density SNP arrays, we identified several homozygous genomic regions one of which included the SPATA7 gene. Several mutations in SPATA7 have been reported for various forms of retinal dystrophy, including Leber congenital amaurosis (LCA) and juvenile RP. PCR-based sequence content mapping, long-distance PCR amplifications, and subsequent sequencing analysis revealed a homozygous 63.4 kb large deletion that encompasses the 5' part of the SPATA7 gene including exons 1-5. The mutation showed concordant segregation with the phenotype in the family as expected for autosomal recessive mode of inheritance and is consistent with a diagnosis of juvenile RP. We report a novel homozygous large deletion in SPATA7 associated with juvenile RP in a consanguineous Israeli Muslim Arab family. This is the first larger deletion mutation reported for SPATA7.

The effect of TIMP-1 on the cone mosaic in the retina of the rat model of retinitis pigmentosa.

The array of photoreceptors found in normal retinas provides uniform and regular sampling of the visual space. In contrast, cones in retinas of the S334ter-line-3 rat model for RP migrate to form a mosaic of rings, leaving large holes with few or no photoreceptors. Similar mosaics appear in human patients with other forms of retinal dystrophy. In the current study, we aimed to investigate the effect of tissue inhibitor of metalloproteinase-1 (TIMP-1) on the mosaic of cones in S334ter-line-3 rat retinas. We focused on TIMP-1 because it is one of the regulators of the extracellular matrix important for cellular migration. Immunohistochemistry was performed to reveal M-opsin cone cells (M-cone) and the results were quantified to test statistically whether or not TIMP-1 restores the mosaics to normal. In particular, the tests focused on the Voronoi and nearest-neighbor distance analyses. Our tests indicated that TIMP-1 led to significant disruption of the M-opsin cone rings in S334ter-line-3 rat retinas and resulted in almost complete homogeneous mosaics. In addition, TIMP-1 induced the M-cone spatial distribution to become closer to random with decreased regularity in S334ter-line-3 rat retinas. These findings confirm that TIMP-1 induced M-cone mosaics in S334ter-line-3 to gain homogeneity without reaching the degree of regularity seen in normal retinal mosaics. Even if TIMP-1 fails to promote regularity, the effects of this drug on homogeneity appear to be so dramatic that TIMP-1 may be a potential therapeutic agent. TIMP-1 improves sampling of the visual field simply by causing homogeneity.

A Homozygous Mutation in theTUBGene Associated with Retinal Dystrophy and Obesity

Inherited retinal dystrophies are a major cause of childhood blindness. Here, we describe the identification of a homozygous frameshift mutation (c.1194_1195delAG, p.Arg398Serfs*9) in TUB in a child from a consanguineous UK Caucasian family investigated using autozygosity mapping and whole-exome sequencing. The proband presented with obesity, night blindness, decreased visual acuity, and electrophysiological features of a rod cone dystrophy. The mutation was also found in two of the proband's siblings with retinal dystrophy and resulted in mislocalization of the truncated protein. In contrast to known forms of retinal dystrophy, including those caused by mutations in the tubby-like protein TULP-1, loss of function of TUB in the proband and two affected family members was associated with early-onset obesity, consistent with an additional role for TUB in energy homeostasis.

Report of a Novel Mutation in CRB1 in a Lebanese Family Presenting Retinal Dystrophy

Purpose: To identify the genetic basis of a recessive inheritance form of retinal dystrophy (RD) in a Lebanese family.Materials and methods: Clinical data were recorded for five patients of the 14 family members. Genetic linkage was carried out using Affymetrix 250 K Nspl SNP array followed by sequencing.Results: The patients showed variable phenotypes ranging from Leber Congenital Amaurosis (LCA) to progressive forms of Retinitis Pigmentosa (RP). A 46.1 Mb chromosomal region at chromosome 1q23.3-32.2 was identified by homozygosity mapping. This region contained the Crumbs homologue-1, CRB1, a gene responsible for recessive retinal dystrophies. CRB1 is required for photoreceptor morphogenesis, and it has been associated with RP and LCA. Sequencing of CRB1 revealed two mutations: a novel deletion in exon 6 (c.1772_1775delGCAT; p.C591Sfs*28) and a missense mutation in exon 7 (c.2234C > T; p.T745M).Conclusion: We report a novel CRB1 mutation in inherited RD in a Lebanese family, and confirm the considerable phenotype heterogeneity that may exist between individuals sharing the same mutations.

Chromatic pupillometry as highly sensitive testing method of photoreceptor function in retinal dystrophies

AbstractPurpose Objective methods for the characterization of photosensitive cells are highly needed in patients with retinal dystrophies. The pupil light reflex is driven by rod, cone, and intrinsic photosensitive retinal ganglion cell (ipRGC) input. The aim of this study is to analyze two protocols of chromatic pupillometry with differing stimulus paradigms to gather isolated functional information of the three cell populations in patients with different forms of retinal dystrophies.Methods The study group comprised 60 patients with different forms of retinal dystrophies, and 32 healthy probands. Patients were grouped according to their electroretinography (ERG) data. A custom made binocular chromatic pupillometer (Bino I, AMTech) connected to the Colordome Ganzfeld stimulator (Diagnosys LLC) was used to assess changes in pupil diameter in response to red (640nm) and blue (462nm) light stimuli.Results Patients who had no measurable scotopic ERG also had the most reduced yet often still measurable rod‐weighted pupil responses (PR), while patients with abnormal or normal scotopic ERG had reduced or normal rod‐weighted PR. Similarly, patients with no measurable photopic ERG had reduced but still measurable cone‐weighted PR, while patients with abnormal of normal photopic ERG had mostly normal cone‐weighted PR. Reduced ipRGC‐weighted PR could not be correlated with the ERG classification.Conclusion In the absence of a measurable ERG, chromatic pupillometry generates important functional and quantifiable data on residual rod and cone activity. These data show that this technique should be added to the panel of examination tools for the characterisation of retinal dystrophies and for quantifying the clinical benefit of experimental treatment protocols.

In Vivo Imaging of the Photoreceptor Mosaic in Retinal Dystrophies and Correlations with Visual Function

To relate in vivo microscopic retinal changes to visual function in patients who have various forms of retinal dystrophy. The UC Davis Adaptive Optics (AO) fundus camera was used to acquire in vivo retinal images at the cellular level. Visual function tests consisting of visual fields, multifocal electroretinography (mfERG), and contrast sensitivity were measured in all subjects by using stimuli that were coincident with areas imaged. Five patients with different forms of retinal dystrophy and three control subjects were recruited. Cone densities were quantified for all retinal images. In all images of diseased retinas, there were extensive areas of dark space between groups of photoreceptors, where no cone photoreceptors were evident. These irregular features were not seen in healthy retinas, but were apparent in patients with retinal dystrophy. There were significant correlations between functional vision losses and the extent to which these irregularities, quantified by cone density, occurred in retinal images. AO fundus imaging is a reliable technique for assessing and quantifying the changes in the photoreceptor layer as disease progresses. Furthermore, this technique can be useful in cases where visual function tests provide borderline or ambiguous results, as it allows visualization of individual photoreceptors.

Mutation screening of three candidate genes, ELOVL5, SMAP1 and GLULD1 in autosomal recessive retinitis pigmentosa

Retinitis pigmentosa (RP) is the most common form of retinal dystrophy. It is featured by a great clinical and genetic heterogeneity. Different patterns of inheritance exist, such as autosomal dominant and recessive, X-linked and digenic. RP25, a locus for autosomal recessive retinitis pigmentosa (arRP), the most frequently inherited form of RP, was mapped to chromosome 6q between D6S257 and D6S1644 microsatellite markers. ELOVL5, SMAP1 and GLULD1 were selected on the basis of their location, tissue expression and/or function. ELOVL5 is implicated in the elongation of long chain fatty acids, including docosahexanoic acid (DHA), which constitutes 50% of the fatty acids of the outer segment of the photoreceptor. SMAP1 (stromal membrane associated protein 1) was found to be located within RP25 locus and is expressed in retina. GLULD1, glutamate-ammonia ligase (glutamine synthase) domain containing 1, plays a key role in the uptake and metabolism of glutamate in the retina. The absence of pathogenic mutations after molecular analysis argues against the implication of ELOVL5, SMAP1 and GLULD1 in the development of RP25 phenotype. Nevertheless, we could not rule them out as good candidates for other retinal degeneration mapping to the same chromosomal region.

Mutations in RDH12 encoding a photoreceptor cell retinol dehydrogenase cause childhood-onset severe retinal dystrophy.

We identified three consanguineous Austrian kindreds with 15 members affected by autosomal recessive childhood-onset severe retinal dystrophy, a genetically heterogeneous group of disorders characterized by degeneration of the photoreceptor cells. A whole-genome scan by microarray analysis of single-nucleotide polymorphisms (ref. 2) identified a founder haplotype and defined a critical interval of 1.53 cM on chromosome 14q23.3-q24.1 that contains the gene associated with this form of retinal dystrophy. RDH12 maps in this region and encodes a retinol dehydrogenase proposed to function in the visual cycle. A homozygous 677A-->G transition (resulting in Y226C) in RDH12 was present in all affected family members studied, as well as in two Austrian individuals with sporadic retinal dystrophy. We identified additional mutations in RDH12 in 3 of 89 non-Austrian individuals with retinal dystrophy: a 5-nucleotide deletion (806delCCCTG) and the transition 565C-->T (resulting in Q189X), each in the homozygous state, and 146C-->T (resulting in T49M) and 184C-->T (resulting in R62X) in compound heterozygosity. When expressed in COS-7 cells, Cys226 and Met49 variants had diminished and aberrant activity, respectively, in interconverting isomers of retinol and retinal. The severe visual impairment of individuals with mutations in RDH12 is in marked contrast to the mild visual deficiency in individuals with fundus albipunctatus caused by mutations in RDH5, encoding another retinal dehydrogenase. Our studies show that RDH12 is associated with retinal dystrophy and encodes an enzyme with a unique, nonredundant role in the photoreceptor cells.

The Y99C mutation in guanylyl cyclase-activating protein 1 increases intracellular Ca2+ and causes photoreceptor degeneration in transgenic mice.

Guanylyl cyclase-activating proteins (GCAPs) are Ca2+-binding proteins that activate guanylyl cyclase when free Ca2+ concentrations in retinal rods and cones fall after illumination and inhibit the cyclase when free Ca2+ reaches its resting level in the dark. Several forms of retinal dystrophy are caused by mutations in GUCA1A, the gene coding for GCAP1. To investigate the cellular mechanisms affected by the diseased state, we created transgenic mice that express GCAP1 with a Tyr99Cys substitution (Y99C GCAP1) found in human patients with a late-onset retinal dystrophy (Payne et al., 1998). Y99C GCAP1 shifted the Ca2+ sensitivity of the guanylyl cyclase in photoreceptors, keeping it partially active at 250 nM free Ca2+, the normal resting Ca2+ concentration in darkness. The enhanced activity of the cyclase in the dark increased cyclic nucleotide-gated channel activity and elevated the rod outer segment Ca2+ concentration in darkness, measured by using fluo-5F and laser spot microscopy. In different lines of transgenic mice the magnitude of this effect rose with the Y99C GCAP1 expression. Surprisingly, there was little change in the rod photoresponse, indicating that dynamic Ca2+-dependent regulation of cGMP synthesis was preserved. However, the photoreceptors in these mice degenerated, and the rate of the cell loss increased with the level of the transgene expression, unlike in transgenic mice that overexpressed normal GCAP1. These results provide the first direct evidence that a mutation linked to congenital blindness increases Ca2+ in the outer segment, which may trigger the apoptotic process.

An integrated genetic approach to identify candidate genes for human chromosome 6q-linked retinal disorders.

In recent years the field of retinal gene discovery has experienced an explosion. An estimated 10,000-30,000 genes are thought to be expressed in the human retina (Shimizu-Matsumoto et al., 1997), with nearly 5,000 retinal transcripts catalogued from expressed sequence tag (EST) datasets (Bortoluzzi et al., 2000) and over 26,000 different transcripts represented in retina serial analysis of gene expression (SAGE) libraries (Sharon et al, 2002). A wide variety of methods have been developed and utilized to define novel retinal genes, particularly in an effort to identify genes targeted in human retinopathies. To date there are 144 diseases of the retina described that have been mapped to human chromosomal locations, and an additional 41 human disorders involving some form of retinal dystrophy for which the genetic map locations have yet to be determined (RetNet Retinal Information Networkhttp://www.sph.uth.tmc.edu/retnet/;Online Mendelian Inheritance in Man (OMIM)http://www.ncbi.nlm.nih.gov/omim/). Despite recent efforts to discover novel genes by analyzing increasingly greater volumes of information arising from human genomic sequence data organization and expression studies, the disease genes for less than one-half of these conditions have at present been cloned. While some of these disorders may be attributed to allelic heterogeneity, a significant number of genes that account for retinal degenerative phenotypes remain to be defined.

Abnormal cone synapses in human cone-rod dystrophy

ObjectiveLittle is known of the cytopathology of photoreceptors in human inherited retinal dystrophies that initially affect the central retina, including the macula. The current study sought to determine the cytologic features of dysfunctional cone and rod photoreceptors, as well as the pattern of degeneration of the cells in representative cases of central retinal dystrophy. Study designComparative human tissue study. MaterialsFour human donor eyes with the following forms of central retinal dystrophy: cone-rod dystrophy (CRD), central areolar choroidal dystrophy, Bardet-Biedl syndrome, and cone dystrophy-cerebellar ataxia. The cytologic features of retinal photoreceptors in these eyes were compared with those in an eye with retinitis pigmentosa and six normal human eyes. Methods and outcome measuresImmunocytochemistry and electron microscopy were used to evaluate the retinal histopathology in the donor eyes. ResultsCone numbers were decreased in the case of CRD, particularly in the central and far peripheral retina, and both cone and rod outer segments were slightly shortened. Occasional degenerate cones had dense cytoplasm and pyknotic nuclei dislocated sclerad to the external-limiting membrane. The most prominent alteration in this retina was marked enlargement and distortion of the cone photoreceptor pedicles, which contained reduced numbers of synaptic vesicles. The retina with central areolar choroidal dystrophy contained a few cones with similarly abnormal synapses. However, comparable cone synapse abnormalities were not observed in the cases of Bardet-Biedl syndrome, cone dystrophy-cerebellar ataxia, retinitis pigmentosa, or in the normal retinas. ConclusionsThe functional consequences of the cone synapse abnormalities in CRD are not known but may correlate with the electroretinographic abnormalities documented in some cases of CRD. To our knowledge, comparable synapse changes have not been noted in either rods or cones in other forms of retinal dystrophy, including retinitis pigmentosa, suggesting that different cytopathologic mechanisms may be involved.

Molecular genetics of human retinal dystrophies.

Retinal dystrophies are a heterogeneous group of diseases in which the retina degenerates, leading to either partial or complete blindness. The severe and clearly hereditary forms, retinitis pigmentosa (RP) and various macular degenerations, affect approximately 1 in 3000 people, but many more suffer from aging macular dystrophy in later life. Patients with RP present with narrowing visual fields and night blindness, while those with diseases of the macula lose central vision first. Even before the advent of molecular genetics it was evident that these were heterogeneous disorders, with wide variation in severity, mode of inheritance and phenotype. However, with the widespread application of linkage analysis and mutation detection techniques, a complex underlying pathology has now been revealed. In total, 66 distinct non-overlapping genes or gene loci have been implicated in the various forms of retinal dystrophy, with more being reported regularly in the literature. Within the category of non-syndromic RP alone there are at least 22 genes (and probably many more) involved, with further allelic heterogeneity arising from different mutations in the same gene. This complexity presents a problem for those involved in counselling patients, and also compounds the search for therapies. Nevertheless, several lines of research raise the hope of generic treatments applicable to all such patients, while the greater understanding of normal visual function that arises from genetic studies may open up new avenues for therapy.

Exclusion of CAG repeat expansion as the cause of disease in autosomal dominant retinitis pigmentosa families.

The involvement of genes with expanded tracts of (CAG)n in some neurodegenerative diseases is well established. Whether genes containing these motifs could also have a role in degenerative diseases affecting...

A ninth locus (RP18) for autosomal dominant retinitis pigmentosa maps in the pericentromeric region of chromosome 1.

We studied a large Danish family of seven generations in which autosomal dominant retinitis pigmentosa (adRP), a heterogeneous genetic form of retinal dystrophy, was segregating. After linkage had been excluded to all known adRP loci on chromosomes 3q, 6p, 7p, 7q, 8q, 17p, 17q and 19q, a genome screening was performed. Positive lod scores suggestive of linkage with values ranging between Z = 1.58-5.36 at theta = 0.04-0.20 were obtained for eight loci on proximal 1p and 1q. Close linkage without recombination and a maximum lod score of 7.22 at theta = 0.00 was found between the adRP locus (RP18) in this family and D1S498 which is on 1q very near the centromere. Analysis of multiply informative meioses suggests that in this family D1S534 and D1S305 flank RP18 in interval 1p13-q23. No linkage has been found to loci from this chromosomal region in six other medium sized adRP families in which the disease locus has been excluded from all known chromosomal regions harbouring an adRP gene or locus suggesting that there is (at least) one further adRP locus to be mapped in the future.