Search

The name retinitis pigmentosa (RP) describes a heterogeneous group of inherited progressive retinal dystrophies, primarily affecting the peripheral retina. Patients experience night blindness and visual field loss, often leading to complete blindness. RP can be inherited in autosomal dominant, autosomal recessive, X-linked, mitochondrial and genetically more complex modes. To date, 39 loci have been implicated in non-syndromic RP, for which 30 of the genes are known. Many of these can be grouped by function, giving insights into the disease process. These include components of the phototransduction cascade, proteins involved in retinol metabolism and cell-cell interaction, photoreceptor structural proteins and transcription factors, intracellular transport proteins and splicing factors. Current knowledge of each grouping is reviewed briefly herein and consistent patterns of inheritance, which may have functional significance, are noted. The complexity of these diseases has in the past made it difficult to counsel patients or to envisage widely applicable therapies. As a more complete picture is emerging however, possibilities exist for streamlining screening services and a number of avenues for possible therapy are being investigated.

The RP9 form of autosomal dominant retinitis pigmentosa (adRP) maps to a locus on human chromosome 7p14. We now report two different disease associated mutations in a previously unidentified human gene, the mouse orthologue of which has been characterised by its interaction with the Pim-1 oncogene. In the original linked family we identified the missense mutation H137L. A second missense mutation, D170G, was found in a single RP patient. The putative RP9 gene appears to be expressed in a wide range of tissues, but its function is unknown and a pathogenic mechanism remains to be determined.

Retinitis pigmentosa (RP) is a genetically heterogeneous disorder characterized by progressive degeneration of the peripheral retina leading to night blindness and loss of visual fields. With an incidence of approximately 1 in 4000, RP can be inherited in X-linked, autosomal dominant or autosomal recessive modes. The RP13 locus for autosomal dominant RP (adRP) was placed on chromosome 17p13.3 by linkage mapping in a large South African adRP family. Using a positional cloning and candidate gene strategy, we have identified seven different missense mutations in the splicing factor gene PRPC8 in adRP families. Three of the mutations cosegregate within three RP13 linked families including the original large South African pedigree, and four additional mutations have been identified in other unrelated adRP families. The seven mutations are clustered within a 14 codon stretch within the last exon of this large 7 kb transcript. The altered amino acid residues at the C-terminus exhibit a high degree of conservation across species as diverse as humans, Arabidopsis and trypanosome, suggesting that some functional significance is associated with this part of the protein. These mutations in this ubiquitous and highly conserved splicing factor offer compelling evidence for a novel pathway to retinal degeneration.

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal diseases which affects approximately 1 in 3500 people worldwide. RP is initially characterized by night blindness followed by progressive degeneration of the retina, often culminating in legal or complete blindness in the later decades of life (Heckenlively et al., 1997). To date 11 autosomal dominant (adRP), 13 autosomal recessive (arRP), 5 X-linked (xlRP), and one digenic form of retinitis pigmentosa have been identified (RetNet). While several disease-associated genes have been identified, the majority of genes remain unknown. Recently we identified the gene and mutations responsible for the RP1 form of autosomal dominant retinitis pigmentosa located on chromosome 8q (Sullivan et al., 1999; Pierce et al., 1999, Guillonneau et al., 1999).

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.

We report on the analysis of a human gene homologous to the rat ventral prostate.1 protein (RVP.1), which is transcriptionally induced in the regressing rat prostate after castration. EST database searching and Northern blotting reveal that this is one of at least four different members of a gene family in the human genome that produce transcripts of 3.4, 2.4, 1.9, and 1.2 kb, expressed in a wide range of tissues. Three other members of this gene family have already been mapped to chromosomes 7q, 17p, and 22q and reported either as anonymous ESTs or as full-length clones. We have now characterized a fourth member (assigned the gene now characterized a fourth member (assigned the gene name C7orf1 by GDB) and localized it also to chromosome 7q. C7orf1 is almost identical over much of its length to the reported ORF of RVP.1 while the other family members are more divergent from RVP.1. The genomic sequence of C7orf1 is intron-less, is spanned by a CpG low-methylation island, and has two noncoding, nonpolymorphic STR regions immediately adjacent to the open reading frame, one 5' and one 3'. The presence of a NotI restriction site in the coding sequence results in a deficiency in the IMAGE cDNA libraries, as a result of which the 3' end of the gene is not in the EST databases. The putative 220-amino-acid protein shows 89% identity to the amino terminus of rat RVP.1. Like rat RVP.1, it has four hydrophobic potential membrane-spanning regions, but it lacks 60 amino acid residues at its carboxyl terminus relative to rat RVP.1. Nevertheless, gene-specific primers from this transcript amplified a product in human cDNAs from several different tissues; its size corresponds to the 1.2-kb transcript seen on a Northern blot, and identical ESTs from several different tissues exist in the databases. It therefore seems likely that C7orf1 is the closest human homologue of rat RVP.1.

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 the retina, which is also neural in origin, is unknown. We investigated (CAG)n expansions as a cause of disease in a panel of eight autosomal dominant retinitis pigmentosa (ADRP) pedigrees, including families known to map to the RP9, RP11, and RP13 loci, using the technique known as "repeat expansion detection" (RED). An expansion was detected in one of the unlinked families, but it did not segregate with the disease and was thus nonpathogenic. Expansions were not detected in any other families. In conclusion, expanded (CAG)n repeats are not the cause of disease in the families we have studied, but given the high level of heterogeneity in RP and in retinal degenerations in general they remain strong candidates for involvement in other forms of retinal dystrophy.

Comment on ‘cosegregation of two unlinked mutant alleles in some cases of autosomal dominant familial exudative vitreoretinopathy’

Introduction Multi-factorial aetiology of schizophrenia has an undeniably large genetic component. Attempts to elucidate its genetics with large case control studies have met with limited success and other approaches are warranted. Method & results In an extended family (pedigree 1) in which two sets of siblings - children of a brother and sister - are intermarried; six members with DSM-IV schizophrenia share a 6MB region of homozygosity on chromosome 13q. One out of twelve genes at this locus shows a sequence change in its promoter region. Download : Download full-size image [Pedigree 1] Another family (pedigree 2) with two affected brothers has revealed two loci of homozygosity on chromosomes 5 and 9. Download : Download full-size image [Pedigree 2] A third family with nine cases of psychosis is being investigated. Conclusion An approach which focuses on families with multiple cases in one generation and evidence of consanguinity in parents may be particularly successful for identifying recessive genes.

3 páginas, 2 figuras, 2 tablas.-- et al., A form of autosomal dominant retinitis pigmentosa (ADRP) mapping to chromosome 17p has been reported in a single large South African family. We now report a new family with severe early onset ADRP which maps to 17p. Linkage and haplotype analysis in this family places the ADRP locus in the 5 cM interval between markers AFMc024za5 and D17S1845, confirming the data obtained in the South African family. The discovery of a second 17p linked family may imply that this is one of the more common loci for dominant RP. In addition, the confirmation of an RP diagnosis at this locus is of interest since loci for a dominant cone dystrophy and Leber's congenital amaurosis (LCA1) have recently been linked to the same markers. While the cone dystrophy locus may be allelic with RP, our data and that of Goliath et al show that distinct genes are responsible for dominant RP and Leber's congenital amaurosis on chromosome 17p., We thank the Wellcome Trust (grant numbers 035535/2/92/Z and 042375/Z/941Z) for funding this research.

6 páginas, 3 figuras, 1 tabla.-- et al., The dominant retinitis pigmentosa locus RP9 has previously been localized to 7p13-p15, in the interval D7S526-D7S484. We now report refinement of the locus to the interval D7S795-D7S484 and a YAC contig of approximately 4.8 Mb spanning this region and extending both distally and proximally from it. The contig was constructed by STS content mapping and physically orders 29 STSs in 28 YAC clones. The order of polymorphic markers in the contig is consistent with a genetic map that has been assembled using haplotype data from the CEPH pedigrees. This contig will provide a primary resource for the construction of a transcriptional map of this region and for the identification of the defective gene causing this form of adRP., We thank the Wellcome Trust (Grant 035535/Z/92/Z) and the Foundation Fighting Blindness of the U.S.A. for funding. We also acknowledge the contribution made to this research by the UK Human Genome Mapping Project Resource Centre, the Reference library Database, and Foundation Jean Dausset (CEPH).

Whilst the majority of inherited diseases have been found to be caused by single base substitutions, small insertions or deletions (

RESULTS. Principal component (PC) analysis of the Raman spectra identified 50 major biochemical profiles, but only PCs that made significant contributions to variation within rdd and wt retina were mapped. These significant PCs were shown to arise from DNA, various fatty acids, melanin, and a number of proteins. Distinct patterns of GFAP immunostaining and a larger population of TUNEL-positive nuclei were observed in the rdd versus wt retina. CONCLUSIONS. This study has demonstrated that Raman microscopy can discriminate between major retinal biomolecules, thus providing an unbiased account of how their composition varies due to the impact of the MPDZ null mutation in the rdd chick relative to expression in the normal wt retina. (Invest Ophthalmol Vis Sci. 2012;53:413‐420) DOI:10.1167/ iovs.11-8591 A premature stop codon in the multiple PDZ domain protein (MPDZ) gene has been identified as the mutation responsible for pathology in the retinal degeneration and dysplasia (rdd) chick and analogous mutations have been identified in patients with human retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). 1 MPDZ participates in tight junction formation with the extracellular proteins, occludin and claudin, and intracellular docking proteins, zonula occludens 1 (ZO-1) and ZO-2. Collectively, these proteins determine the permeability of tight junctions in many tissues, including the retina where MPDZ has been localized to the outer limiting membrane (OLM). 1‐3 Effects of the MPDZ null mutation in the rdd chick retina were first observed at embryonic day (E)18, with the onset of abnormal undulation in the outer plexiform layer (OPL) and associated disarrangement of the maturing outer nuclear layer (ONL). These retinal abnormalities are accentuated at P1 and accompanied by apparent detachment of the disorganized photoreceptor outer segments from the retinal pigmented epithelium (RPE). The rdd chicks are sighted at hatching but no vision is detectable 10 weeks after hatching. 4,5 Proteomic analysis of retina from E12 to posthatch day (P)1 revealed that several proteins were differentially expressed during retinogenesis and with the onset of degeneration in the rdd chick; this would suggest that the MPDZ mutation may have an impact on retinal development before

Juvenile onset dominant optic atrophy (DOA) is the most common inherited optic atrophy with a variable prevalence of between 1 in 10 000 (Denmark) and 1 in 50 000.1,2 The majority of cases have been shown to have mutations in the OPA1 gene on chromosome 3.3–5 Reduced visual acuity of insidious onset, temporal pallor of the optic disc, centrocaecal scotoma, and generalised dyschromatopsia are the key clinical features.6 Recent studies, however, have shown that penetrance within families is much lower than first realised and the assignment of status using clinical criteria alone can result …

We read with interest the article by Durnian and Clark who presented a retrospective cohort of infants that fell outside evidence level B guidelines for screening retinopathy of prematurity (ROP) and we wish to discuss some further points.1 The data presented in table 1 highlight that all 11 babies would be missed if screening was according to level B evidence and 2 of these would still be missed using the good practice points evidence. An alternative conclusion would be that if the guidelines had been amended to screen infants under 32 weeks or 1251 g then one extra baby would have been missed (who fortunately did not require treatment). It is also debatable based on the information presented, if any of the babies absolutely required treatment as others …

The most prevalent group of genetically determined progressive retinopathies, currently affecting approximately 1.5 million people, is collectively termed retinitis pigmentosa (RP). RP describes a heterogeneous group of disorders primarily involving photoreceptor degeneration. The rapid development of highly informative DNA polymorphisms as genetic markers throughout the human genome has facilitated the localisation of genes responsible for many human disorders such as RP. Furthermore, techniques for rapid identification of sequence variation have provided an effective means of investigating genes that are considered to be ‘candidates’ for a particular disease in a given patient population. Such techniques have been successfully applied to the study of RP. In this paper, we will deal mainly with the recent developments in the autosomal dominantly inherited forms of RP, in particular highlighting the extensive genetic heterogeneity which we now know to be inherent in this group of diseases.

Retinitis pigmentosa is an inherited progressive disease which is a major cause of blindness in western communities. It can be inherited as an autosomal dominant, autosomal recessive, or X-linked recessive disorder. In the autosomal dominant form (adRP), which comprises about 25% of total cases, approximately 30% of families have mutations in the gene encoding the rod photoreceptor-specific protein rhodopsin. This is the transmembrane protein which, when photoexcited, initiates the visual transduction cascade. So far, 41 single-base-pair (bp) substitutions, one two-bp substitution, and four deletions ranging from 3 to 42 bp have been identified in this gene. These mutations do not appear to be significantly clustered in a specific part of the protein, but occur in all three major domains, namely the intradiscal, transmembrane, and cytoplasmic regions. Different mutations appear to cause differences in the severity of the disease, though there is considerable variability in severity even within the same family, at least in certain of these mutations. Identification of all the mutations involved in rhodopsin-RP should allow accurate and early detection of affected individuals, informed genetic counselling, as well as furthering our knowledge of the disease process involved.

We read with interest the recent article of Papanikolaou et al 1 describing a possible inherited form of Salzmann's nodular …

Purpose To define the phenotype of the retinal degeneration associated with mutations in the CERKL gene. Methods Six patients (ages, 26-54 years) from three unrelated families with CERKL mutations were studied clinically and by electroretinography, kinetic, and chromatic static perimetry, autofluorescence (AF) imaging, and optical coherence tomography (OCT). Results Three siblings were homozygotes for p.R257X mutation; two siblings were compound heterozygotes for p.R257X and a novel p.C362X mutation; and one patient had only p.R257X mutation identified to date. There was a spectrum of severity: from mild visual acuity loss to light perception; from full kinetic fields with relative central scotomas to remnant peripheral islands; from reduced ERGs (some with negative waveforms) to nondetectable signals. Maculopathy showed residual foveal islands or extensive central rod and cone scotomas. With AF imaging, there was evidence of hyperautofluorescence at earlier and hypoautofluorescence at later disease stages. Peripheral function was generally less affected than central function. With OCT there were small foveal islands of outer nuclear layer (ONL) in those with preserved acuity. Eccentric to an annular region with no discernible ONL, there could be ONL in the midperiphery. At early disease stages, ganglion cell layer thickness was less affected than ONL. Later disease stages were accompanied by inner nuclear layer and nerve fiber layer abnormalities. Conclusions CERKL mutations are associated with widespread retinal degeneration with prominent maculopathy. The clinical presentation is that of an autosomal recessive cone-rod dystrophy. Photoreceptor loss appears at all stages of disease and inner laminopathy complicates the phenotype at later stages.

Purpose Strabismus is a common eye disorder with a prevalence of 1% to 4%. Comitant strabismus accounts for approximately 75% of all strabismus, yet more is known about the less common incomitant disorders. Comitant strabismus is at least partly inherited, but only one recessive genetic susceptibility locus, on chromosome 7p, has been identified in one family. The purpose of this study was to determine the frequency of STBMS1 as a cause of primary nonsyndromic comitant esotropia (PNCE). Methods Twelve families were recruited within the UK Hospital Eye Service as children attended for treatment of PNCE. All consenting persons were clinically assessed, and DNA was sampled. Chromosome 7 microsatellite markers were genotyped in all 12 families, and LOD scores were calculated under recessive and dominant models. Results One family was linked to STBMS1; in three, linkage was significantly excluded; and the remainder were uninformative. Twenty-six members from three generations of the linked family were analyzed further. Five family members were defined as affected; two had esotropia with an accommodative element; and three underwent strabismus surgery and appeared to have had an infantile/early-onset esotropia. A maximum LOD score of 3.21 was obtained under a dominant mode of inheritance; a recessive model gave an LOD score of 1.2. Conclusions This study confirms that PNCE can result from sequence variants in an unknown gene at the STBMS1 locus. However, this locus accounts for only a proportion of cases, and other genetic loci remain to be identified. In contrast with the previously reported family, the pedigree described in this study is consistent with dominant rather than recessive inheritance at the STBMS1 locus.

Real-time PCR is increasingly being adopted for RNA quantification and genetic analysis. At present the most popular real-time PCR assay is based on the hybridisation of a dual-labelled probe to the PCR product, and the development of a signal by loss of fluorescence quenching as PCR degrades the probe. Though this so-called 'TaqMan' approach has proved easy to optimise in practice, the dual-labelled probes are relatively expensive. We have designed a new assay based on SYBR-Green I binding that is quick, reliable, easily optimised and compares well with the published assay. Here we demonstrate its general applicability by measuring copy number in three different genetic contexts; the quantification of a gene rearrangement (T-cell receptor excision circles (TREC) in peripheral blood mononuclear cells); the detection and quantification of GLI, MYC-C and MYC-N gene amplification in cell lines and cancer biopsies; and detection of deletions in the OPA1 gene in dominant optic atrophy. Our assay has important clinical applications, providing accurate diagnostic results in less time, from less biopsy material and at less cost than assays currently employed such as FISH or Southern blotting.

Editor,—Congenital hereditary endothelial dystrophy (CHED) and posterior polymorphous corneal dystrophy (PPCD) are phenotypically distinct diseases of the corneal endothelium. Linkage analysis has mapped a locus for autosomal dominant PPCD to chromosome 20p11.1 Subsequently, other researchers placed a locus for autosomal dominant CHED (designated CHED1 by the human genome mapping workshop) in an overlapping genetic interval,2 suggesting that these two disorders may be allelic variants of the same defective gene. However, CHED is more commonly inherited as an autosomal recessive (AR) disease,3 and linkage analysis in a large consanguineous recessive Saudi Arabian pedigree excluded CHED1 as the causative locus.4 Genetic heterogeneity in this condition was further confirmed by linkage analysis in a large consanguineous Irish pedigree5 in which a second CHED genetic locus (CHED2) was subsequently localised more distally at 20p13.6 We now present a Pakistani pedigree with …

Primary congenital glaucoma (PCG) is an autosomal-recessive condition characterized by high intraocular pressure (IOP), usually within the first year of life, which potentially could lead to optic nerve damage, globe enlargement, and permanent loss of vision. To date, PCG has been linked to three loci: 2p21 (GLC3A), for which the responsible gene is CYP1B1, and 1p36 (GLC3B) and 14q24 (GLC3C), for which the genes remain to be identified. Here we report that null mutations in LTBP2 cause PCG in four consanguineous families from Pakistan and in patients of Gypsy ethnicity. LTBP2 maps to chromosome 14q24.3 but is around 1.3 Mb proximal to the documented GLC3C locus. Therefore, it remains to be determined whether LTBP2 is the GLC3C gene or whether a second adjacent gene is also implicated in PCG. LTBP2 is the largest member of the latent transforming growth factor (TGF)-beta binding protein family, which are extracellular matrix proteins with multidomain structure. It has homology to fibrillins and may have roles in cell adhesion and as a structural component of microfibrils. We confirmed localization of LTBP2 in the anterior segment of the eye, at the ciliary body, and particularly the ciliary process. These findings reveal that LTBP2 is essential for normal development of the anterior chamber of the eye, where it may have a structural role in maintaining ciliary muscle tone.

Cone-rod dystrophy (CRD) is an inherited progressive retinal dystrophy affecting the function of cone and rod photoreceptors. By autozygosity mapping, we identified null mutations in the ADAM metallopeptidase domain 9 (ADAM9) gene in four consanguineous families with recessively inherited early-onset CRD. We also found reduced photoreceptor responses in Adam9 knockout mice, previously reported to be asymptomatic. In 12-month-old knockout mice, photoreceptors appear normal, but the apical processes of the retinal pigment epithelium (RPE) cells are disorganized and contact between photoreceptor outer segments (POSs) and the RPE apical surface is compromised. In 20-month-old mice, there is clear evidence of progressive retinal degeneration with disorganized POS and thinning of the outer nuclear layer (ONL) in addition to the anomaly at the POS-RPE junction. RPE basal deposits and macrophages were also apparent in older mice. These findings therefore not only identify ADAM9 as a CRD gene but also identify a form of pathology wherein retinal disease first manifests at the POS-RPE junction.

Dominant optic atrophy (DOA) is the most common form of autosomally inherited optic neuropathy.1 The disease typically presents in childhood with slow bilateral loss of visual acuity, visual field defects, abnormal colour discrimination, and pallor of the optic discs. The majority of DOA families published to date have shown linkage to a major locus on chromosome 3q28 ( OPA1 ). The OPA1 gene was recently identified and found to encode a ubiquitously expressed, dynamin related GTPase.2,3 In order to determine the mutation spectrum of OPA1 in DOA, we and others have screened the coding exons and their flanking splice sites in large patient cohorts.4–7 Over 60 different mutations have been reported, most of which are specific to individual families. It has been speculated that haploinsufficiency is the cause of disease,3–6 but to date there has been no evidence to prove that this mechanism, rather than aberrant function of mutated proteins, is responsible for the disease. Using a combined approach of single stranded conformational polymorphism and heteroduplex analysis, we detected mutations in 57% (20/35) of our affected DOA patients.5 Additional DNA samples from an Australian family, in which no OPA1 mutation was identified in the above mutation screen, have recently been obtained enabling further investigation of the cause of disease in this family. All available family members underwent clinical evaluation to determine their disease status. This included best corrected visual acuity (BCVA), assessment of colour vision with Isihara plates and/or City University testing, automated perimetry (Humphrey Field Analyzer, San Leandro, CA), and dilated fundus examination with stereo disc photography. The ocular phenotype observed was typical of DOA with visual acuity reduction ranging from mild to moderate, mild to moderate colour vision disturbance, and visual field analysis ranging from normal to mild paracentral …

Dominant optic atrophy (DOA) is the commonest form of inherited optic neuropathy. Although heterogeneous, a major locus has been mapped to chromosome 3q28 and the gene responsible, OPA1, was recently identified. We therefore screened a panel of 35 DOA patients for mutations in OPA1. This revealed 14 novel mutations and a further three known mutations, which together accounted for 20 of the 35 families (57%) included in this study. This more than doubles the number of OPA1 mutations reported in the literature, bringing the total to 25. These are predominantly null mutations generating truncated proteins, strongly suggesting that the mechanism underlying DOA is haploinsufficiency. The mutations are largely family-specific, although a common 4 bp deletion in exon 27 (eight different families) and missense mutations in exons 8 (two families) and 9 (two families) have been identified. Haplotype analysis of individuals with the exon 27 2708del(TTAG) mutation suggests that this is a mutation hotspot and not an ancient mutation, thus excluding a major founder effect at the OPA1 locus. The mutation screening in this study also identified a number of asymptomatic individuals with OPA1 mutations. A re-calculation of the penetrance of this disorder within two of our families indicates figures as low as 43 and 62% associated with the 2708del(TTAG) mutation. If haploinsufficiency is the mechanism underlying DOA it is unlikely that this figure will be mutation-specific, indicating that the penetrance in DOA is much lower than the 98% reported previously. To investigate whether Leber's hereditary optic neuropathy (LHON) could be caused by mutations in OPA1 we also screened a panel of 28 LHON patients who tested negatively for the three major LHON mutations. No mutations were identified in any LHON patients, indicating that DOA and LHON are genetically distinct.