A Spontaneous Nonhuman Primate Model of Best Vitelliform Macular Dystrophy

Abstract

Purpose : Mutations in the BEST1 gene are the most frequent cause of Best vitelliform macular dystrophy (BVMD), an autosomal dominant inherited macular degeneration disease. The pathogenic mechanism of BVMD remains unclear, primarily hindered by the lack of animal models that fully replicate the human condition. This study aims to explore spontaneous degenerative maculopathy in nonhuman primates (NHPs) with cone-rich macula, providing potential novel models to expedite the development of therapies for BVMD patients.

Methods : The clinical phenotype of a 6.8-year-old male macaca fascicularis exhibiting spontaneous maculopathy was longitudinally assessed over 2 years using optical coherence tomography (OCT), fundus photography, and electroretinogram (ERG). Whole genome sequencing (WGS) and allele frequency (AF) analysis were employed for genotyping in the macaque population. In silico predictions, in vitro whole-cell patch clamping, and biochemical assays were conducted to examine the functional alterations associated with the identified mutation. Histopathologic changes were explored post-sacrifice.

Results : Both eyes of the affected animal displayed yolk-like lesions and clefts with subretinal deposits in the macular region, exhibiting a gradual progression consistent with the previtelliform stage of BVMD in human patients. A rare missense heterozygous mutation c.979C>G (p.Q327E) in BEST1 was identified, with an allele frequency of 1/260 in the macaque population. Q327E mutation was predicted to be deleterious, displaying mislocalized subcellular position and significantly smaller chloride currents compared to wild-type BEST1. Consistently, histopathology analyses revealed a substantial reduction in BEST1 protein expression in the retinal pigment epithelium (RPE) of the affected eyes, alongside pronounced cleft formation and lipid deposition between the RPE and photoreceptor outer segments (OS) layer in the macular area. Additionally, retracted RPE apical projections and accumulated OS fragments, were observed, indicating a disruption of the RPE-OS interface and RPE phagocytosis of cone OS as a pathological mechanism.

Conclusions : We have identified a spontaneous nonhuman primate model of BVMD carrying a novel heterozygous Q327E mutation in the BEST1 gene. The NHP model suggests that loss of function in BEST1 and disruption of the RPE-photoreceptor interface contribute to the pathogenesis of BVMD.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.