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In majority of the XLR cases, pathogenic variants in Retinoschisin 1 (<jats:italic>RS1<\/jats:italic>) 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\u2010coding region of <jats:italic>RS1<\/jats:italic> was screened by PCR\u2010Sanger 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.<\/jats:p>","DOI":"10.1002\/ajmg.a.63327","type":"journal-article","created":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T09:54:53Z","timestamp":1686822893000},"page":"2524-2535","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Identification and molecular characterization of two recurrent missense mutations in the <scp><i>RS1<\/i><\/scp> gene in two families with X\u2010linked retinoschisis from North India"],"prefix":"10.1002","volume":"191","author":[{"given":"Souradip","family":"Chatterjee","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics, Institute of Science Banaras Hindu University  Varanasi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shashank","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Institute of Science Banaras Hindu University  Varanasi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laxmi","family":"Kirola","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Institute of Science Banaras Hindu University  Varanasi India"},{"name":"Centre for Cellular and Molecular Biotechnology Amity Institute of Biotechnology  Noida India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abhishek","family":"Chandra","sequence":"additional","affiliation":[{"name":"Chandra Eye Care and Research Centre  Varanasi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashim","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Institute of Science Banaras Hindu University  Varanasi India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1339-8535","authenticated-orcid":false,"given":"Mousumi","family":"Mutsuddi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Institute of Science Banaras Hindu University  Varanasi India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,6,15]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0147653"},{"key":"e_1_2_10_3_1","first-page":"291","article-title":"Clinical findings and RS1 genotype in 90 Chinese families with X\u2010linked retinoschisis","volume":"26","author":"Chen C.","year":"2020","journal-title":"Molecular Vision"},{"key":"e_1_2_10_4_1","first-page":"3614","article-title":"A novel clinical presentation of congenital X\u2010linked retinoschisis","volume":"52","author":"Eadie J. 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