Genetic and clinical characteristics of PROM1-related retinal degeneration in Korean

Abstract

This scientific report aims to comprehensively describe the genetic and clinical characteristics of PROM1-related retinal degeneration in Korean patients. Medical records of patients diagnosed with retinal dystrophy who underwent comprehensive ophthalmologic examination and genetic testing at Samsung Medical Center between January 2016 and April 2023 were retrospectively reviewed. Genetic testing included targeted gene panel sequencing and Sanger sequencing, with diagnosis based on the presence of a “Likely Pathogenic” or “Pathogenic Variant” in the PROM1 gene, as determined by the ACMG criteria. The study identified seven patients from five unrelated families with PROM1-related retinal degeneration, all carrying the autosomal dominant variant PROM1 p.R373C; no other PROM1 gene variants were detected. All patients exhibited degenerative retinal area within the macula, with peripheral retinal degeneration observed in five patients. Substantial interfamilial and intrafamilial variability was observed in the extent of macular and peripheral degeneration. Ultra-widefield autofluorescence imaging and fluorescein angiography aided in the detection of mild peripheral degeneration in one case. In conclusion, the autosomal dominant variant PROM1 p.R373C constitutes a significant proportion of PROM1-related retinal degeneration cases in the Korean population. The observed clinical heterogeneity may suggests the potential influence of additional genetic, epigenetic, and environmental factors on disease phenotypes.

Retinoid Synthesis Regulation by Retinal Cells in Health and Disease

“…Indeed, gene variants unrelated to the retinoid cycle that affect lipid handling in RPE cells are also associated with retinal dystrophies involving early cone loss [134,138,142,144,150,157,236] and the metabolic reprogramming of RPE cells [144,157]. This evidence indicates that A2E may impact RPE cells by impairing lipid handling [139][140][141] and activating innate immunity [144,145,[147][148][149].…”

“…However, Prominin-1 is also a cholesterol-binding protein promoting axonal regeneration by down-regulating neuron cholesterol synthesis via the Smad pathway [137]. It is intriguing that, although not involved in the retinoid cycle, PROM1 pathogenic variants in Stargardt 4 patients may cause autosomal dominant macular degeneration with increased macular fundus autofluorescence [138].…”

Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes

“…In this regard, mutations in this gene account for 1 to 9.5% of AR CORD worldwide [ 8 , 55 , 56 ], 2% of AR RP and 4% AD RP in Spain [ 57 ]. In Asia, a cohort of 10 Japanese patients, considered as large cohort, were related to 3 variants, all exhibiting AD inheritance [ 58 ]; similarly, 10 Korean patients were all related to the same variant (p.Arg373Cys), also showing AD inheritance [ 25 ]. In Europe, the largest cohort included 25 Spanish patients, but only 7 of them underwent the main outcome measures FAF and OCT [ 22 ]; meanwhile, the second largest study included only 19 European patients [ 23 ].…”

“…Even within the same family, it has been reported substantial differences in the severity and extension of retinal degeneration. This clinical heterogeneity may be due to the influence of modifier genes, epigenetic and environmental factors [ 25 ].…”

Posterior Polar Annular Choroidal Dystrophy: Genetic Insights and Differential Diagnosis in Inherited Retinal Diseases

“…Transmembrane protein [48,49] Involved in photoreceptor disk morphogenesis [48,49] 4p15.32 [48,49] TIMP3 Metallopeptidase inhibitor [50] Involved in ocular development [50] 22q12.3 [50] CCD2D2A Binding domain protein [3] Uncertain significance, possibly related to cilia structure and function [3] 4q21.1 [3] CEP78 Centrosomal protein [51] May be involved in ciliary functions [51] 9q21.13 [51] NR2E3 Nuclear receptor [3,21,22,52] Key transcription factor for photoreceptor development [3,21,22,52] 15q23 [21,22] PCARE Ciliary and actin-associated protein [3,23,53] Probably associated with the primary cilium of the outer segment [3,23,53] 2p23.2 [53]…”