Small nuclear RNAs (snRNAs) combine with specific proteins to generate small nuclear ribonucleoproteins (snRNPs), the building blocks of the spliceosome. U4 snRNA forms a duplex with U6 and, together with U5, contributes to the tri-snRNP spliceosomal complex. Variants in RNU4-2, which encodes U4, have recently been implicated in neurodevelopmental disorders. Here we show that heterozygous inherited and de novo variants in RNU4-2 and in four RNU6 paralogs (RNU6-1, RNU6-2, RNU6-8 and RNU6-9), which encode U6, recur in individuals with nonsyndromic retinitis pigmentosa (RP), a genetic disorder causing progressive blindness. These variants cluster within the three-way junction of the U4/U6 duplex, a site that interacts with tri-snRNP splicing factors also known to cause RP (PRPF3, PRPF8, PRPF31), and seem to affect snRNP biogenesis. Based on our cohort, deleterious variants in RNU4-2 and RNU6 paralogs may explain up to ~1.4% of otherwise undiagnosed RP cases. This study highlights the contribution of noncoding RNA genes to Mendelian disease and reveals pleiotropy in RNU4-2, where distinct variants underlie neurodevelopmental disorder and retinal degeneration.
PURPOSE. We examined the choroid in both eyes from a donor with multifocal geographic atrophy (GA), enlarged choroidal vessels, and choroidal neovascularization (CNV) secondary to age-related macular degeneration, using histology and immunohistochemistry, and we correlated the findings with multimodal clinical imaging. METHODS. A Caucasian woman with bilateral GA was followed clinically for 5 years, until 6 years prior to her death at age 93. To correlate clinical and histologic features, the right eyecup was photographed before dissecting the posterior pole. Choroidal blood vessels were labeled with Ulex europaeus agglutinin-1 (UEA-1) lectin following retinal pigment epithelium removal and imaged by confocal microscopy. Selected regions were embedded and sectioned for histologic staining. The left eye was used for ultrastructure analysis. RESULTS. The posterior pole exhibited areas of atrophy surrounded by mottled retinal pigment epithelium overlying calcified drusen. Confocal imaging of the UEA-1 lectin- labeled choroidal flatmounts showed limited visualization of the submacular vasculature, consistent with masking by basal laminar and lipid-rich deposits seen in histologic sections. In well-labeled regions of the posterior pole, the choriocapillaris was attenuated and widely separated by markedly thickened, hyalinized intercapillary pillars. Venules and veins appeared dilated, and arteries exhibited arteriosclerotic changes. A choroidal neovascular complex was observed superior to the optic nerve head near the atrophic border; the adjacent choriocapillaris was attenuated. CONCLUSIONS. In this single case of multifocal GA, choroidal thickening and large-caliber outer choroidal vessels coexisted with marked choriocapillaris degeneration and adjacent neovascularization. These observations suggest that structural choroidal enlargement does not preclude choriocapillaris failure and may be associated with ischemic and neovascular phenotypes.
PURPOSE:To describe atypical fundus autofluorescence (FAF) patterns in geographic atrophy (GA) secondary to age-related macular degeneration (AMD) with associated age-related choroidal atrophy (ARCA). METHODS:Multimodal imaging of two cases using (pseudo-)color fundus photography, optical coherence tomography (OCT), and FAF used with blue and green excitation wavelengths on several devices ( Spectralis, Heidelberg and (ultra-)widefield [UWF] FAF [ California, Optos and EIDON, iCare ]). RESULTS:Two female patients with foveal-involving GA secondary to AMD were assessed. All eyes demonstrated concurrent features indicative of ARCA on multimodal imaging including a paucity of choroidal vasculature, reduced choroidal pigmentation, macular pigmentary changes, peripapillary atrophy, and subretinal drusenoid deposits. Clinically, progression of GA with coalescence of lobular lesions was observed. Notably, UWF FAF with green-( California ) and blue excitation wavelengths ( California and EIDON ) revealed atypical patterns characterized by isofluorescent FAF signals (indistinguishable from surrounding tissue) or hyperautofluorescent GA lesions. In these cases, blue excitation wavelengths were more effective than green light for delineating GA, owing to increased contrast from hypoautofluorescence related to macular pigment surrounding the lesion. CONCLUSION:In patients with GA and concomitant ARCA, atypical FAF patterns on UWF imaging complicate the accurate delineation and monitoring of GA. Atypical FAF patterns appear because of the properties of the confocal apertures and postprocessing features of UWF imaging that allow for the detection of scleral autofluorescence in patients with reduced choroidal vasculature, pigment, and thickness. In patients with concomitant ARCA, multimodal imaging plays a crucial role in precisely identifying and tracking GA progression.
PURPOSE. In geographic atrophy (GA) of AMD, comparing photoreceptor disintegrity and RPE loss in optical coherence tomography (OCT) and microscopy may elucidate atrophy expansion and suggest imaging biomarkers. METHODS. One eye of a 93-year-old woman with bilateral drusen-driven GA of AMD was analyzed. RPE loss and reduced photoreceptor segment integrity (rPSi) was quantified automatically in clinical OCT volumes over a five-year period ending six years pre-mortem. In transmission electron micrographs of the outer junctional zone (OJZ) and a comparison area, tissue component volumes were measured. RESULTS. By OCT, rPSi area exceeded RPE loss at baseline. Yearly RPE loss (2.432 mm2) exceeded rPSi (1.770 mm2) as these areas converged. By microscopy, the mean distance between the external limiting membrane (ELM) and RPE basal lamina in the OJZ was 50% of the comparison. Volumes of interphotoreceptor space, outer segments, inner segment myoids, inner segment ellipsoids, and in-layer RPE were 16%, 17%, 25%, 50%, and 104%, respectively, of the comparison. Cone inner segments exhibited fragmented and translocating mitochondria over drusen and at the ELM descent. In some OCT scans, the descent appeared especially hyperreflective. CONCLUSIONS. In this first clinicopathologic correlation of an AMD eye with a known GA growth rate, the area of rPSi (a composite representing photoreceptor shortening, disorganization, altered waveguiding, and true cell death) exceeds the area of RPE loss. The OJZ exhibits dysmorphic but continuous RPE. Photoreceptors degenerate from the outer segments inward. Mitochondrial fission and translocation at the ELM descent may be visible clinically.
This case report describes the potential phenotypic features in 2 patients with enhanced S-cone syndrome: rosettelike and whorllike lesions.
