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PubMed2026

Molecular diagnostic yield and barriers in inherited retinal diseases: a retrospective cohort study.

OBJECTIVE: To evaluate the diagnostic yield of panel-based genetic testing for inherited retinal diseases (IRDs) and identify barriers to molecular resolution. DESIGN: Retrospective cohort. PARTICIPANTS: A total of 404 patients with clinically confirmed IRDs who were evaluated at the Adult Inherited Retinal Dystrophy Service, Ontario, Canada (October 2021-September 2024). METHODS: Patients underwent targeted massive parallel sequencing panel testing. Diagnostic yield was calculated, and unresolved cases were reviewed. Associations between yield, phenotype, ethnicity, and sex were assessed using χ² analysis. RESULTS: Of 685 referrals, 570 had confirmed IRDs. After we excluded 140 pending results and 26 patients who declined testing, 404 patients were analyzed. At referral, 94 patients (23.2%) had a previous molecular diagnosis, and 138 (34.0%) were diagnosed through clinic-initiated testing, giving an overall yield of 57.4%. Yield varied significantly by phenotype (χ², P = 1.4 × 10⁻⁶), from 94.4% in vitelliform macular dystrophies to 25.0% in vitreoretinopathies, with no sex association (P = 1.0). Disease-causing variants were identified in 83 IRD-associated genes, most frequently ABCA4, USH2A, and BEST1. Of 172 unresolved cases, 62 (36.0%) had negative panels, and 110 (63.9%) were inconclusive, including 30 with unphased pathogenic variants in recessive genes and 10 with high-suspicion variants of uncertain significance. Key barriers included limited family availability for phasing, restricted access to functional assays, and lack of public coverage for whole-exome or whole-genome sequencing. CONCLUSIONS: Massive parallel sequencing-based panel testing achieved a 57% diagnostic yield in this IRD population. Success was strongly phenotype-dependent with substantial heterogeneity. Whole-exome sequencing, whole-genome sequencing, family segregation, and functional genomics could improve diagnostic outcomes and management.

Humans↗

PubMed2025

Biallelic null variants in C19orf44 cause a unique late-onset retinal dystrophy phenotype characterized by patchy perifoveal chorioretinal atrophy.

PURPOSE: To identify the genetic cause for disease in individuals affected with inherited retinal disease and to characterize their retinal phenotype and the properties of the underlying gene. METHODS: Participants underwent a comprehensive ophthalmological evaluation, including best-corrected visual acuity, visual field testing, fundus autofluorescence, optical coherence tomography, and electroretinography. Genetic analyses included exome, genome, and Sanger sequencing. Gene expression pattern was analyzed by reverse transcription-polymerase chain reaction. Localization of the encoded protein in cells and in the human retina was examined by immunofluorescence staining. RESULTS: Four different pathogenic variants in C19orf44 were identified in 15 biallelic individuals from 11 unrelated families. The most common variant was c.549_550del p.(Ser185ProfsTer2). Most individuals were affected with a unique clinical phenotype characterized by late-onset patchy perifoveal chorioretinal atrophy and electroretinographic features of rod-cone degeneration. C19orf44 is expressed in various human tissues, including the retina, where it was found in the outer nuclear layer and in the outer plexiform layer. In cultured cells (hTERT RPE-1 and HeLa) and in human primary fibroblasts, C19orf44 is found in the nucleus, and it is downregulated during mitosis. CONCLUSION: Based on our results, C19orf44 is crucial for normal human retinal function, and pathogenic variants in this gene are associated with autosomal recessive inherited retinal disease.

Humans↗

PubMed2026

Development of RS1-specific ACMG/AMP variant classification criteria with pilot variant curation.

Gene-based therapies are being developed for retinal diseases, including RS1-related X-linked retinoschisis. Therefore it is essential to determine which variants are pathogenic and which are benign when enrolling patients. The Clinical Genome Resource (ClinGen) X-Linked Inherited Retinal Diseases (XLRD) Variant Curation Expert Panel (VCEP) brings together clinician scientists, molecular biologists, and geneticists to apply their expertise and review the clinical, genetic, population, and functional evidence for variants. American College of Medical Genetics (ACMG) guidelines have been modified for RS1 to develop a highly systematic and conservative framework for evaluating variants. The curation process involves applying 28 different codes, each with 4 strength levels (very strong, strong, moderate, supporting) across different domains of phenotype, population data, computational assessment, functional impact, and segregation. With RS1-specific rules, a total of 54 pilot variants were tested. These included 47 variants in ClinVar. Of these 21 variants were re-classified: 2 likely pathogenic variants and one likely benign were changed to variants of uncertain significance and 4 previously unclassified variants were changed to pathogenic, likely pathogenic and likely benign. Other changes resolved conflicts or multiple classifications.

Humans↗

PubMed2026

Whole-Exome Sequencing in a Consanguinity-Enriched South Indian Retinitis Pigmentosa Cohort: Diagnostic Yield and Molecular Spectrum.

PURPOSE: To determine the molecular diagnostic yield, variant spectrum, inheritance architecture, and influence of consanguinity on whole-exome sequencing outcomes in a South Indian retinitis pigmentosa (RP) cohort. DESIGN: Prospective, registry-based cohort study. SUBJECTS: A total of 113 affected participants were enrolled through the Aravind Registry for Inherited Diseases of the Eye, including 109 unrelated probands and 4 affected relatives from already represented families. Primary analyses were restricted to the 109 unrelated probands. METHODS: Whole-exome sequencing was performed using a clinical exome workflow. Variants were interpreted using American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria and cases were categorized as solved, possibly solved, inconclusive, or unsolved using prespecified inheritance-aware rules. MAIN OUTCOME MEASURES: Molecular diagnostic yield, distribution of implicated genes and variant classes, inheritance architecture, and diagnostic yield stratified by consanguinity status. RESULTS: Among the 109 unrelated probands, mean age at testing was 39.3 ± 14.1 years and 58.7% were male. Whole-exome sequencing identified 186 distinct rare variants across 92 inherited retinal disease genes, including 26 pathogenic and 33 likely pathogenic variants. A molecular diagnosis was established in 50 of 109 probands (45.9%), including 42 solved and 8 possibly solved cases; 45 (41.3%) were inconclusive and 14 (12.8%) remained unsolved, including 4 (3.7%) in whom no candidate variant was identified. EYS, USH2A, and ADGRV1 were the most frequently implicated genes. Autosomal recessive (AR) disease predominated (44/50, 88.0%). Consanguineous AR cases were exclusively homozygous (17/17); notably, 68.0% of nonconsanguineous AR cases were also homozygous (P = 0.013). Diagnostic yield was higher in consanguineous probands (51.4% vs. 41.7%), without reaching significance. Recurrent alleles included an established South Asian founder variant (MFSD8 c.1361T>C) and candidate founder alleles in EYS (c.4321C>T) and ADGRV1 (c.14329C>T). CONCLUSIONS: Whole-exome sequencing established a molecular diagnosis in nearly half of this South Indian RP cohort and revealed a predominantly recessive, homozygosity-enriched architecture shaped by consanguinity. These findings define a region-specific variant landscape to support clinical interpretation, genetic counseling, and future trial enrollment in this underrepresented population. FINANCIAL DISCLOSURES: The authors have no proprietary or commercial interest in any materials discussed in this article.

Consanguinity↗

PubMed2026

Homozygous initiation codon-altering complex variant causes rapid-onset chorioretinopathy phenotype in ABCA4 disease.

PURPOSE: To characterize the clinical phenotype associated with a homozygous start codon-altering complex variant in the ABCA4 gene and evaluate its severity and prognosis in the context of Stargardt disease. METHODS: Patient records were retrospectively reviewed for homozygous ABCA4 start codon variants. Patients underwent ophthalmic exam, multimodal imaging, full-field electroretinography (ffERG), and inherited retinal disease panel testing. Structural and functional retinal assessments were reviewed to determine phenotype severity. RESULTS: Three brothers of Ashkenazi Jewish descent presented with profound early-onset vision loss beginning at age 7, with best-corrected visual acuity reduced to counting fingers or hand motion by early adulthood. Imaging revealed widespread macular atrophy, extensive intraretinal pigment migration, and near-complete foveal outer nuclear layer loss. ffERG demonstrated extinguished scotopic and photopic responses. The patients were found to be homozygous for a complex ABCA4 allele containing the start codon variant c.[1A > G;6089G > A]. These features were consistent with the rapid-onset chorioretinopathy phenotype, previously associated with null ABCA4 alleles. CONCLUSIONS: This report characterizes the clinical findings in patients homozygous for the c.[1A > G;6089G > A] variant in ABCA4, confirming its association with a severe, rapid-onset chorioretinopathy phenotype. The data support the pathogenic nature of this complex allele and expands the genotype-phenotype correlational spectrum of ABCA4-related disease, with implications for prognosis and genetic counseling.

Humans↗

PubMed2026

Systematic discovery of retina-enriched Rik genes identifies 1190005I06Rik as a novel modulator of visual signalling.

BACKGROUND: High‑throughput transcriptome projects have revealed thousands of mammalian genes with little or no functional annotation. Among these are hundreds of loci assigned provisional “Rik” identifiers following discovery in the RIKEN cDNA annotation effort. Although often dismissed as genomic dark matter, such genes may encode tissue‑restricted proteins that modulate physiologic functions and influence disease. The retina is a highly specialised neural tissue and a common site of inherited disorders; understanding its molecular repertoire could illuminate novel therapeutic avenues. METHODS: We integrated bulk RNA‑seq from ten adult mouse tissues, evolutionary and domain analysis, single‑cell RNA‑seq, and CRISPR/Cas9 gene disruption to systematically catalogue protein‑coding Rik genes enriched in the retina and test the function of a representative gene. RESULTS: A rigorous differential expression analysis identified 44 Rik genes with robust retina‑specific expression compared with nine non‑retinal tissues. Many of these genes lack orthologues beyond rodents, while others show broad conservation, illustrating a continuum from lineage‑restricted to conserved retinopathy candidates. Single‑cell transcriptomics revealed that these genes are expressed across retinal cell types, with the highest aggregate expression in cone photoreceptors and inner interneurons. To evaluate physiological significance, we generated a 1190005I06Rik knockout mouse. Although retinal architecture appeared normal, loss of 1190005I06Rik enhanced electroretinogram b‑wave amplitudes and altered light‑avoidance behaviour, indicating that this previously uncharacterised gene acts as a negative modulator of visual signalling. CONCLUSIONS: We present a curated atlas of retina‑enriched Rik genes and demonstrate that 1190005I06RIK modulates retinal circuit function. This resource expands the molecular landscape of the retina and provides new candidates for the genetic basis of inherited retinal disease. Our findings underscore that unannotated genes may exert measurable effects on sensory processing and warrant systematic exploration in the context of human ocular disorders.

Animals↗

PubMed2025

Founder Homozygous Nonsense CREB3 Variant and Variable-Onset Retinal Degeneration.

IMPORTANCE: Uncovering the genetic basis of inherited retinal diseases (IRDs) can enhance both diagnostic accuracy and the development of targeted treatment strategies. OBJECTIVE: To evaluate the association between a homozygous nonsense variant in CREB3 with IRDs. DESIGN, SETTING, AND PARTICIPANTS: Thirteen patients with a clinical diagnosis of retinitis pigmentosa or cone-rod degeneration were analyzed by whole-genome sequencing (WGS) and whole-exome sequencing (WES). Clinically, patients presented with 2 main phenotypes, rod-cone and cone-rod dystrophies, demonstrating variable electrophysiological and fundoscopic findings. Expression analysis was performed on patient-derived skin fibroblasts using the reverse transcription-polymerase chain reaction and Western blot analysis, and by interrogating previously published retinal single-cell RNA sequence data. Immunohistochemistry staining was performed on wild-type mouse retinal sections using an anti-CREB3 antibody. Patients with variable phenotypes of IRDs were recruited from 3 medical centers in Israel and Italy. Ophthalmologists clinically diagnosed patients at the relevant medical centers and referred them for genetic screening. WES and WGS were performed at different national and international centers, and the findings of the previously unreported gene were shared between investigators. EXPOSURES: CREB3 and IRDs. MAIN OUTCOMES AND MEASURES: The main outcome was evidence supporting an association between CREB3 and IRD. Measures included WES, WGS, and immunohistochemistry staining. RESULTS: A founder homozygous nonsense variant in CREB3 (c.881G>A, p.Trp294*) was identified in 13 patients from 4 unrelated families; 12 descendent from North-African Jewish origins and 1 from Italian origins. All patients manifested retinal degeneration with varying ages at onset. In patient-derived fibroblasts, the variant mRNA transcript generated a truncated CREB3 protein. Expression analysis and immunohistochemistry staining revealed CREB3 RNA and protein expression in various retinal cell types, indicating its vital role in photoreceptor function. CONCLUSIONS AND RELEVANCE: This study found an association between CREB3 and IRDs. CREB3 was previously shown to be upregulated following ultraviolet radiation. This might contribute to the extensive clinical variability observed in this relatively large cohort of homozygous patients with the same truncated variant.

Humans↗

PubMed2026

XXYLT1 and Mendelian Retinal Dystrophy.

IMPORTANCE: Substantial unexplained heritability remains for pathogenic inherited retinal disease (IRD) variants. Application of genome-wide association studies (GWAS) could help identify causal genes in rare diseases. OBJECTIVE: To leverage a GWAS for the discovery of IRD-associated genes. DESIGN, SETTING, AND PARTICIPANTS: This GWAS analysis was combined with replication of findings in 2 independent IRD cohorts. The study was conducted from January 2024 to December 2025 in a multicenter setting through FinnGen, 100 000 Genomes Project, and the National Health Service Genomic Medicine Service combined with clinical cohort from the Oulu University Hospital. Using IRD criteria from the International Classification of Diseases, 9th and 10th Revisions, 540 individuals with IRD and 473 945 control individuals were identified in the FinnGen study. For validation of FinnGen results, 49 patients were recruited from Oulu University Hospital. Results were further validated in 2 individuals identified from the UK cohort. MAIN OUTCOMES AND MEASURES: The GWAS and proteomics analysis were performed in the FinnGen cohort. Sanger and whole-genome sequencing and RNA approaches were used in a clinical IRD cohort to validate pathogenicity of the identified XXYLT1 variant. RESULTS: This GWAS identified 13 recessive loci reaching genome-wide significance (defined as P < 5 × 10-8). Of these, 4 (near or within XXYLT1, ANKRD10, DYM, and CBLN4) had not been associated with IRD, including the XXYLT1 c.505-1G>C founder variant. This variant was further genotyped in the clinical replication cohort, leading to identification of 5 more homozygous individuals from 4 families. The phenotype was consistent with a cone-rod or macular dystrophy, with visual deterioration, cystoid macular edema and/or schisislike macular abnormalities. The effect of the XXYLT1 c.505-1G>C variant was further investigated using RNA sequencing and complementary DNA amplicon sequencing, demonstrating exon 2 skipping and a loss-of-function effect. These findings were replicated in an independent population identifying 2 patients from the UK harboring a homozygous XXYLT1 c.766G>A, p.(Glu256Lys) missense variant. CONCLUSIONS AND RELEVANCE: This GWAS identified an association between XXYLT1 and IRD. These results affirm that GWAS in a founder population can be used as a potential tool for the discovery of rare mendelian disease genes and that XXYLT1 should be considered in clinical IRD gene panels.

Humans↗

PubMed2025

Biallelic loss-of-function variants in C19orf44 lead to retinal degeneration.

BACKGROUND: Inherited retinal diseases (IRDs) are a group of disorders often resulting in progressive vision loss, ultimately leading to blindness. A significant portion of their genetic causes remain unresolved, partly due to undiscovered disease-associated genes or variants. This study aimed to identify novel genetic links to IRDs. METHODS: All patients underwent comprehensive ophthalmological evaluation, including retinal imaging (fundus autofluorescence and macular optical coherence tomography) and electroretinogram testing. Whole exome sequencing and whole genome sequencing were performed on patients with clinically unsolved IRD, and data were analysed using an in-house pipeline to identify causal variants. Subsequently, Sanger sequencing was performed to confirm identified variants. RESULTS: Three unrelated patients from Europe, Middle East and East Asia were identified with unique late-onset retinal degeneration (Stargardt-like phenotype) associated with biallelic loss-of-function (LoF) variants in C19orf44 (HGNC: 26141), a gene of unknown function. The homozygous variant NM_032207.2:c.549_550del;p.Ser185Profs*2 was identified in two unrelated patients (European and Middle Eastern). Moreover, an East Asian patient had likely compound heterozygous LoF variants (NM_032207.2:c.1168C>T;p.Gln390*/c.976_977del;p.Leu326Lysfs*15). CONCLUSIONS: Our findings establish C19orf44 as a novel disease-causing gene for IRD with Stargardt-like phenotype, expanding the genetic landscape of retinal degeneration.

Humans↗

PubMed2025

Sex Distributions in the Most Frequent Autosomal Genetic Causes of Retinitis Pigmentosa.

PURPOSE: The purpose of this study was to explore whether sex imbalances are detectable in the most frequent genetic causes of retinitis pigmentosa (RP). METHODS: Databases from centers in three countries (Moorfields Eye Hospital, London; Hospital for Sick Children, Toronto; and Australian Inherited Retinal Disease Registry, Perth, Australia) were searched, quantifying numbers of male and female patients with disease attributed to variants in the six most frequently involved autosomal RP genes. Proportions of female patients (with 95% confidence intervals [CIs]) were calculated for each gene. Two-tailed binomial testing was performed (Bonferroni corrected threshold, P = 0.008) to investigate whether proportions differed significantly from an underlying male:female ratio of 1:1. For genes where the 95% CI did not include 50%, sex distributions were also explored in previously published cohorts. RESULTS: Our search yielded 1454 patients with disease attributable to variants in USH2A (n = 550), RP1 (n = 277), RHO (n = 246), PRPF31 (n = 158), EYS (n = 124), and MYO7A (n = 99). Proportions of female patients (95% CI) for each gene were 46.2% (42.0-50.5%), 49.5% (43.4-55.5%), 55.3% (48.8-61.6%), 63.9% (55.9-71.3%), 39.5% (31.0-48.7%), and 42.4% (32.7-52.8%), respectively. The 95% CI did not include 50% for PRPF31 and EYS; binomial testing revealed P values of 6.24 × 10-4 and 0.025, respectively. Combining with data extracted from previously published cohorts yielded P values of 1.62 × 10-6 and 0.0084, respectively. CONCLUSIONS: We observed a significant preponderance of female patients for PRPF31-associated RP and a preponderance of male patients in those with EYS-associated RP. Our findings suggest that sex is likely to be a modifier affecting penetrance in PRPF31-associated disease and might act in the opposite direction in disease associated with EYS.

Humans↗

PubMed2026

Interindividual variability in immune response to AAV ocular gene delivery across species impedes immunomonitoring.

Adeno-associated viruses (AAVs) have been used in gene therapy, especially for inherited retinal diseases. Despite their effectiveness in gene transduction, immune responses to the AAV capsid and transgene products have been reported, which can compromise both the efficacy and the safety of AAV-mediated therapies. The eye is regarded as an immune-privileged organ where immune activity is constitutively suppressed. Here, we highlight that immunomonitoring in an ocular gene transfer reveals variable immune responses, whatever the species (human clinical trial, nonhuman primates, mice), the site of injection, the cassette, and the dose. We further explored factors contributing to this variability, investigating the potential correlation among immune parameters in a controlled experimental setting. In a syngeneic murine model after a subretinal injection of AAV, our results highlight an interindividual variability of immune parameters, emphasizing the importance of considering inherent variability among individuals when designing personalized therapies.

Animals↗

PubMed2025

Identification of IDH3G, encoding the gamma subunit of mitochondrial isocitrate dehydrogenase, as a novel candidate gene for X-linked retinitis pigmentosa.

PURPOSE: Retinitis pigmentosa (RP) is a genetically heterogeneous group of retinal degenerative disorders characterized by the loss of rod and cone photoreceptors, leading to visual impairment and blindness. To date, to our knowledge, X-linked RP has been associated with variants in 3 genes (RPGR, RP2, and OFD1), whereas genetic defects at 3 loci (RP6, RP24, and RP34) are yet unidentified. The aim of this study was to identify a novel candidate gene underlying X-linked RP. METHODS: Participants were identified from cohorts of genetically unsolved male individuals affected by RP, who underwent genome sequencing, exome sequencing, or candidate gene screening via direct Sanger sequencing at 3 referral centers. Specifically, 2 probands were identified at the National Reference Centre for Rare Retinal Diseases (Paris, France), 2 at the Massachusetts Eye and Ear Hospital (Boston, MA), and 1 at the National Reference Centre for Inherited Sensory Diseases (Montpellier, France). The pathogenicity of the identified variants was assessed using bioinformatic predictions, protein expression analyses, and mitochondrial function assays. RESULTS: We identified 4 rare single-nucleotide variants in IDH3G (HGNC:5386), located at the RP34 locus on the X chromosome, and a complete gene deletion, in 5 unrelated male individuals affected with nonsyndromic RP. The variants segregated with the phenotype in all available family members. In all cases, the disease severity was intermediate. None had high myopia. IDH3G encodes the γ subunit of mitochondrial isocitrate dehydrogenase (IDH3), an enzyme involved in the citric acid cycle, which is expressed in the inner segments of photoreceptors. Variants in IDH3A and IDH3B, encoding the other subunits of IDH3, have already been associated with nonsyndromic autosomal recessive RP. Bioinformatic predictions and functional assays support a pathogenic role for the variants identified in this study, possibly through partial loss of enzymatic activity and mitochondrial function. CONCLUSION: Our findings suggest that variants in IDH3G are a novel cause of X-linked RP.

Humans↗

PubMed2026

Systematic functional evaluation of CNGA1 missense variants associated with retinitis pigmentosa.

BACKGROUND: Missense variants are frequently classified as variants of uncertain significance (VUS) according to the guidelines of the American College of Medical Genetics and Genomics and the Association of Molecular Pathology (ACMG/AMP). Consequently, disease relevance remains elusive, impeding molecular genetic diagnostics, patients` and family genetic counseling, and identification of patients eligible for clinical trials. Functional studies are critical for resolving the clinical significance of VUS. CNGA1 encodes the main subunit of the rod cyclic nucleotide-gated (CNG) channel, a vital component of the phototransduction cascade. Variants in CNGA1 are a rare cause of autosomal recessive retinitis pigmentosa and a phase I/II gene augmentation trial (NCT06291935) is currently ongoing highlighting the necessity to differentiate benign from pathogenic variants. METHODS: CNGA1 missense variants compiled from retinal disease patient cohorts, public databases and literature were functionally investigated using a medium-throughput aequorin-based assay and in vitro minigene splice assays for predicted exonic spliceogenic variants. Functional data were correlated with the in silico prediction of five variant effect predictors (VEPs) and applied to support or revise variants' ACMG/AMP classification. RESULTS: Data mining revealed 86 missense CNGA1 variants - including three novel - most of them lacking functional data; 65.1% of the variants were initially classified as VUS. The aequorin-based assay showed that 72.1% of tested variants significantly impaired CNG channel function and were classified as functionally abnormal, while 23.3% were functionally normal and 5% remained functionally uncertain. Correlation of the functional data with in silico predictions identified AlphaMissense and CPT-1 to be the most suitable tools for assessing CNGA1 missense variants. Using in vitro minigene splice assays, two putative missense variants were shown to induce missplicing. Based on the functional findings, 62.1% of the variants initially classified as VUS were re-categorized as likely pathogenic or likely benign. Furthermore, 93.3% of the variants initially classified as likely pathogenic showed an effect on CNGA1 channel function, confirming their disease relevance and supporting their reclassification as pathogenic. CONCLUSION: This study represents the first comprehensive functional assessment of disease-associated CNGA1 missense variants, thus significantly advancing the understanding of their disease relevance and improving molecular genetic diagnostics in patients.

Humans↗

PubMed1976

Hereditary renal-retinal dysplasia and the medullary cystic disease-nephronophthisis complex.

Nine of 81 members of two families were found to have renal problems. Three patients in one family had renal-retinal dysplasia with probable recessive inheritance. Of the 6 patients in the second family, one received a kidney transplant from his brother who initially had no detectable renal abnormality but later developed renal failure. In this family, the mode of inheritance seems to be dominant. Hereditary renal-retinal dysplasia differs from medullary cystic disease and nephronophthisis in its pattern of uniformly recessive inheritance and its accompaniment by retinitis pigmentosa. Because genetic considerations have important implications in selection of donors for renal transplant, these entities should be considered distinct despite the similarities in their clinical and pathologic features.

Adolescent↗

PubMed1992

Genetic linkage of autosomal dominant neovascular inflammatory vitreoretinopathy to chromosome 11q13.

Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is an inherited eye disease characterized by retinal and iris neovascularization, abnormal retinal pigmentation, anterior chamber and vitreous inflammation, cystoid macular edema, vitreous hemorrhage, and traction retinal detachment. Some of these clinical features are shared by more common, potentially blinding, conditions including diabetic retinopathy, uveitis, and retinitis pigmentosa. Elucidation of the molecular pathogenesis of ADNIV has the potential to provide insight into the mechanisms of these common disorders. One hundred and sixteen members of an eight generation family affected with ADNIV were examined. A combination of slit lamp biomicroscopy, ophthalmoscopy, and electroretinography was used to establish the diagnosis and 34 family members were found to be affected. Blood samples were obtained from thirty-three of these individuals and nine spouses and used for chromosome linkage analysis with denaturing gradient gel and short tandem repeat polymorphisms. Two markers that map to chromosome 11q13 were found to be significantly linked to the ADNIV phenotype. There were no recombinants between the disease phenotype and marker D11S527 and multipoint analysis yielded a maximum LOD score of 11.9 centered on this marker.

Adult↗

PubMed1992

Sick photoreceptors attract activated microglia from the ganglion cell layer: a model to study the inflammatory cascades in rats with inherited retinal dystrophy.

Understanding of neuron-glial interactions in neurodegenerative diseases remains limited, but is of crucial importance for unravelling the etiology of such disorders both in humans and in animals. The present work employed a new, function-dependent technique for examining the role of microglia in rats afflicted with inherited retinal photoreceptor degeneration (strain: royal college of surgeons, RCS). In this rat strain, which served as a surrogate for human inherited retinal photoreceptor dystrophy, the optic nerve was cut and the ganglion cells were retrogradely labelled with the fluorescent dye 4Di-10ASP. The experiment was performed under three different conditions: (1) at the 50th day of postnatal age (P50) when there is ongoing degeneration of photoreceptor cells, (2) at P110 when most photoreceptors were degenerated and (3) at P50 in non-dystrophic rats of the Sprague-Dawley strain. After axotomy-induced ganglion cell death and labelling of activated microglia by phagocytosis of the ganglion cell debris, this study monitored whether the labelled and therefore identifiable microglial cells within the severed ganglion cell layer (GCL) are prompted to migrate and to participate in phagocytosis of debris produced within the endogenously degenerating photoreceptor cell layer (PRL). Massive migration of microglial cells from the GCL to the PRL occurred in dystrophic animals with optic nerve transection at P50. Double-labelling of microglial cells with the fluorescent dye ingested within the GCL and with lipofuscin ingested within the PRL indicated the ability of these cells to perform double-phagocytosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1977

Rat model for hereditary retinal degeneration.

The disorder in Wag/Rij rats is a spontaneous, bilateral retinal deneration. It is characterized by an early onset, slowly progressive degeneration of the photoreceptor cells leading to destruction of the retina. Degeneration affects both rod cells and cone cells, and to a lesser degree the cells in the inner nuclear layer. The remarkable alterations in the retinal pigment epithelium during the course of the disease suggest a profound change in metabolism and function of the pigment epithelium and implicate a possibility of interaction between the pigment epithelium and the photoreceptors. Since degenerated cells have also been observed in the inner nuclear layers, there is a possibility that Muller's cells are involved in the retinal degeneration. Controlled experiments have demonstrated that the disease is not induced by light damaging effects of the retina, and initial breeding experiments suggest that the disease is inheritable, probably as an autosomal dominant trait. The retinal degeneration in Wag/Rij rats is a new, unique system and it is a potentially very useful animal model of retinitis pigmentosa.

Aging↗

PubMed1992

Ceroid lipofuscinosis in the border collie dog: retinal lesions in an animal model of juvenile Batten disease.

Ceroid lipofuscinosis, an inherited disorder of lipopigment accumulation, was identified in a group of Border Collie dogs. The dogs developed mental, motor, and visual signs between age 15 and 22 months and progressed rapidly to severe neurological disease. The principal signs were blindness and gait and behavioural abnormalities with progressive dementia. Lipopigment accumulation was severe in neurones and glial cells of the central nervous system and was present in some visceral cells. Inclusions with variable ultrastructure were common in all cells of the retina, but the pigment accumulation did not damage the retinal architecture. The cytoplasmic inclusions were granular, sudanophilic, eosinophilic, and autofluorescent. Ultrastructural morphology varied, but fingerprint and curvilinear patterns predominated. The retinal lesions in the Border Collies were similar to those in English Setters with ceroid lipofuscinosis, but were much less severe than in juvenile human ceroid lipofuscinosis. This disorder bears a close resemblance to ceroid lipofuscinosis in English Setters and is another useful model for Batten's disease.

Animals↗