Identification and molecular characterization of two recurrent missense mutations in the RS1 gene in two families with X‐linked retinoschisis from North India

Abstract

X‐linked retinoschisis (XLR) is a rare medical condition that involves in the splitting of neurosensory layers and the impairment of vision in the retina. In majority of the XLR cases, pathogenic variants in Retinoschisin 1 (RS1) gene have been implicated in males with an early age of onset during early childhood. In the present study, we have recruited two North Indian families having multiple affected male members, who were diagnosed with XLR. The entire protein‐coding region of RS1 was screened by PCR‐Sanger sequencing and two recurrent pathogenic variants (p.I81N and p.R102Q) were unraveled. The in vitro study of these variants demonstrated the aggregation of mutant RS1 within the endoplasmic reticulum. Furthermore, mutant forms of this protein showed significant intracellular retention, which was evident by the absence of retinoschisin protein fractions in the extracellular media. These inferences were also supported by extensive bioinformatics analysis of the mutants, which showed dramatic conformational changes in the local structure of retinoschisin. Thus, our study suggests that the identified pathogenic variants interfere with proper protein folding, leading to anomalous structural changes ultimately resulting in intracellular retention of retinoschisin within the retina.

The dose-response relationship of subretinal gene therapy with rAAV2tYF-CB-hRS1 in a mouse model of X-linked retinoschisis

“…Over 279 pathogenic variants of the RS1 gene have been linked to XLRS ( 49 ). Gene therapy for RS1 holds significant promise to enhance the lives of these patients.…”

Genotypic and phenotypic diversity in X-linked retinoschisis: Findings from a South Indian patient cohort

“…Furthermore, another proband exhibited the p.R102W mutation, resulting in macular schisis and retinal detachment. [ 28 ] Previous studies indicated a distinct spoke wheel pattern and foveal schisis in a 12-year-old boy with retinoschisis, attributed to the p.R102W mutation. [ 29 ] In addition, a study involving 86 Juvenile X-linked retinoschisis (JXLR) patients in the UK unveiled intrafamilial disparities in visual acuity associated with the same p.R102W mutations.…”