A spontaneous nonhuman primate model of inherited retinal degeneration
Wei Yi, … , Elia J. Duh, Xialin Liu
Wei Yi, … , Elia J. Duh, Xialin Liu
Published May 6, 2025
Citation Information: JCI Insight. 2025;10(12):e190807. https://doi.org/10.1172/jci.insight.190807.
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Research Article Genetics Ophthalmology

A spontaneous nonhuman primate model of inherited retinal degeneration

Abstract

Inherited retinal degenerations (IRDs) are important causes of progressive, irreversible blindness. Hereditary macular diseases, in particular, are significant in their effect on the specialized, central cone photoreceptor–rich macula responsible for high resolution vision. Autosomal dominant Best vitelliform macular dystrophy (BVMD), caused by variants in the BEST1 gene, is one of the most common inherited macular dystrophies. Gene therapies have emerged as promising treatments for IRDs, but a lack of suitable animal models has hindered progress both in treatments and in understanding the mechanisms underlying macular diseases. Here, we report a Macaca fascicularis carrying a heterozygous potential pathogenic BEST1p.Q327E variant that disrupts the BEST1 ion channel by destabilizing the A195 helix, mirroring the structural perturbations seen in certain human pathological mutants. Longitudinal imaging over 2 years revealed progressive macular changes, including subfoveal cleft enlargement, lipid-rich deposit accumulation, retinal pigment epithelium (RPE) disruption, and central-to-peripheral photoreceptor degeneration, recapitulating early human BVMD pathology. Histopathology demonstrated diminished BEST1 expression, attenuation of the RPE-photoreceptor interface, and 2 distinct types of lipid deposits, including heretofore unappreciated cone mitochondrial-enriched lesions, highlighting selective cone mitochondria vulnerability. This is, to our knowledge, the first nonhuman primate model of inherited macular dystrophy, and it links BEST1 mutations, mitochondrial dysfunction, and progressive macular degeneration, offering new insights into BVMD pathophysiology and highlighting its utility for studying disease progression and potential therapeutic interventions.

Authors

Wei Yi, Mingming Xu, Ying Xue, Yingxue Cao, Ziqi Yang, Lingli Zhou, Yang Zhou, Le Shi, Xiaomei Mai, Zehui Sun, Wenjie Qing, Yuying Li, Aolun Qing, Kaiwen Zhang, Lechun Ou, Shoudeng Chen, Elia J. Duh, Xialin Liu

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Figure 1

Identification of a macaque with a heterozygous deleterious BEST1p.Q327E variant.

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Identification of a macaque with a heterozygous deleterious BEST1p.Q327E...
(A) SD-OCT imaging reveals a small subfoveal cleft (as indicated by the yellow arrow) in the abnormal animal (6.8 years old), compared with the age-matched normal macaque (6.8 years old). (B) Fundus images from the mutant macaque did not show significant pathologic changes, including vitelliform lesion. (C) Sanger sequencing showed that the abnormal Macaca fascicularis carries a heterozygous BEST1p.Q327E variant. (D) The allele frequency of the BEST1:c.C979G: p.Q327E variant in Homo sapiens, Macaca mulatta, and Macaca fascicularis. (E) Structural modeling of the human Bestrophin-1 (hBest1) pentamer structure (PDB: 8D1K) showed that substitution of the glutamine (Q) side chain to glutamic acid (E) increases negative charge and enhances its electrostatic interactions with the main chain of K194 in the adjacent protomer. Q327/E327 in protomer 1 and adjacent protomer 5 are showcased with a protein electrostatic potential rendering, ranging from red (–50) to blue (50). (F) Current-voltage relationship of HEK293T cells transiently expressing WT or BEST1 variants, measured by whole-cell patch clamping for calcium-activated chloride ion conductance. The Q327E and A195V exhibited smaller currents compared with the WT. The mock group transfected with empty vectors showed the lowest current signal. Data are presented as mean ± SEM. n = 6–9. P < 0.001 for both Q327E and A195V, compared with WT mfBest1. P values were calculated using 2-way ANOVA. (G) Cotransfection of Q327E and WT BEST1 plasmids in a 1:1 ratio significantly reduced the current from WT BEST1. Data are presented as mean ± SEM. n = 6–10. P < 0.001 for Q327E+WT compared with WT mfBest1. P values were calculated using 2-way ANOVA.