Autosomal Dominant Gyrate Atrophy-Like Choroidal Dystrophy Revisited: 45 Years Follow-Up and Association with a Novel C1QTNF5 Missense Variant

Abstract

We present a long-term follow-up in autosomal dominant gyrate atrophy-like choroidal dystrophy (adGALCD) and propose a possible genotype/phenotype correlation. Ophthalmic examination of six patients from two families revealed confluent areas of choroidal atrophy resembling gyrate atrophy, starting in the second decade of life. Progression continued centrally, reaching the fovea at about 60 years of age. Subretinal deposits, retinal pigmentation or choroidal neovascularization as seen in late-onset retinal degeneration (LORD) were not observed. Whole genome sequencing revealed a novel missense variant in the C1QTNF5 gene (p.(Q180E)) which was found in heterozygous state in all affected subjects. Haplotype analysis showed that this variant found in both families is identical by descent. Three-dimensional modeling of the possible supramolecular assemblies of C1QTNF5 revealed that the p.(Q180E) variant led to the destabilization of protein tertiary and quaternary structures, affecting both the stability of the single protomer and the entire globular head, thus exerting detrimental effects on the formation of C1QTNF5 trimeric globular domains and their interaction. In conclusion, we propose that the p.(Q180E) variant causes a specific phenotype, adGALCD, that differs in multiple clinical aspects from LORD. Disruption of optimal cell-adhesion mechanisms is expected when analyzing the effects of the point mutation at the protein level.

Clinical characteristics of gyrate atrophy compared with a gyrate atrophy-like retinal phenotype

“…5, 8 and 10). 10,11 Macular oedema was also less frequent in the GALRP group, similar to previous reports. 11 In contrast, all patients with GA had macular edema, which had also been observed in other GA patients.…”

“…10,11 Macular oedema was also less frequent in the GALRP group, similar to previous reports. 11 In contrast, all patients with GA had macular edema, which had also been observed in other GA patients. 15 Since only one case with GA revealed centre-involving photoreceptor atrophy on SD-OCT, the decrease in central vision in the other two GA patients was probably caused by a combination of the cystoid macular oedema, the high degree of myopia and / or the onset of cataract.…”

“…Recently, a family affected by a missense variant in the C1QTNF5 gene, a gene previously described only for late-onset retinal degeneration (L-ORD), was reported to show a GALRP rather than a L-ORD phenotype. 11 Thus, there appear to be at least two distinct disease entities: treatable GA with high plasma ornithine levels and, in some cases monogenetic, GALRP with normal plasma ornithine levels that is as yet untreatable. The aim of this study was to examine patients with GA and / or GALRP presenting to three large eye centres and to describe similarities and differences that may help in the differential diagnosis to ensure that the diagnosis of GA is not overlooked.…”

Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration

“…By their interaction with molecules involved in adhesion, ECM regulation and cytoskeletal rearrangements, they play roles in various cellular processes, including adhesion, migration, and signalling 58 and have been implicated in various pathological events, such as angiogenesis in AMD, wound healing and immune cell response and inflammation 59 . Variants in C1QTNF5, a membrane protein involved in cell adhesion and secretion, are associated with lateonset retinal degeneration [60][61][62][63] . The immunoglobulin BSG, an extracellular matrix metalloproteinase inducer which stimulates cells to produce MMPs, plays roles in immune responses and has been implicated in photoreceptor survival 64,65 .…”

Inherited Retinal Diseases

“…A large number of clinical trials targeting various IRD-related genes and mutations are currently ongoing. Comprehensive studies on the clinical spectrum and natural history associated with various IRD-causative genes and mutations are greatly important not only to define prognosis, but also to identify clinical trial endpoints [ 14 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”