Researchers at the Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand, have reported a D126G missense mutation in the RS1 gene, causing X-linked juvenile retinoschisis (XLRS), exclusively detected in Thai patients in a recent study. In their cohort of patients, the mutation appears to provide the highest prevalence in RS1 gene alterations (although the patient population was small), presenting as asymmetrical visual acuity and schisis. The Thai research team have analysed the molecular pathobiology of the D126G mutation and “provides a proof-of-concept on the possible pathogenesis of the RS1 mutation distinctively found in Thai patients, thus laying the foundations for future development of personalised advanced treatment of XLRS.”
X-linked retinoschisis (XLRS) is an uncommon inherited retinal degeneration (IRD), with a prevalent estimate ranging from 1 to 5,000 to 1 in 25,000 cases, mainly affected in males however, a number of female carriers may exhibit the phenotype due to skewed X-inactivation. XLRS is a monogenic X-linked disease that leads to schisis (or splitting) of the neural retina leading to reduced visual acuity caused by mutations in the RS1 gene, encoded by the retinoschisin protein secreted principally in the outer retina. The disorder presents disturbances in central vision, strabismus or nystagmus, affecting from an early age impacting daily function, including difficulty with reading and obtaining a driver’s license. Mutations of the RS1 gene comprise >200 alterations, most of which are missense and the majority occur in exon 4-6, corresponding to the discoidin domain. The researchers in their paper commented that “the phenotypes of XLRS, including clinical presentations and disease progression, are highly variable, making establishment of a genotype-phenotype correlation challenging.”
Clinical analysis showed a very early onset within D126G patients with blurred vision and/or eso/exotropia. Functional analysis In the molecular study of the pathobiology (with D126G) showed a failure of protein secretion attributable to endoplasmic reticulum (ER) retention.
Figure 1. Functional prediction of the RS1 D126G variant – the tertiary structure of the discoidin domain of the wild type RS1 protein (PDB:3JD6) retrieved from the protein database (rcsb.org) and visualized using Pymol. An electrostatic map is transparently overlaid on the tertiary structure, with the negative (red) and positive (blue) potentials. The three amino acid mutations found in our Thai patient cohort are indicated (position 126, 209, and 213). Open access is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, published by Suvannaboon R, et al, entitled: The D126G mutation contributes to the early-onset X-linked juvenile retinoschisis. Sci Rep. 2025 Jan 2;15(1):541.. https://doi.org/10.1038/s41598-024-84161-1
According the researchers, the mutation profiles of RS1 gene “are relatively convenient for gene therapy development as it is a small gene that can be efficiently carried by efficient viral vectors like the adeno-associated virus (AAV).” As a result, the Thai group proposed that “these could serve as the foundation for the future therapeutic development for XLRS. Nonetheless, it is essential to continuously monitor the prospective gene mutations and clinical profiles of this disease.” In summary, their work suggests that a “particular population could immensely benefit the pipeline of personalised treatment design for XLRS.”