Deciphering the impact of ABCA4 genetic variants of unknown significance in inherited retinal disease through computational and functional approaches

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dc.contributor.authorCevik, Senem
dc.contributor.authorJones, Jazzlyn S.
dc.contributor.authorBiswas, Subhasis B.
dc.contributor.authorBiswas-Fiss, Esther E.
dc.date.accessioned2026-01-24T12:20:50Z
dc.date.available2026-01-24T12:20:50Z
dc.date.issued2025
dc.departmentAlanya Alaaddin Keykubat Üniversitesi
dc.description.abstractVariants in the ABCA4 gene are a fundamental cause of several inherited retinal degenerations (IRDs), including Stargardt macular dystrophy, retinitis pigmentosa, and cone-rod dystrophy. These three ABCA4-driven diseases are estimated to cause blindness in 1.4 million people worldwide. As a result, genetic testing of ABCA4 is increasingly common in clinical settings. Of the 4111 identified variants in ABCA4, 1668 are missense, of which 47 % are of unknown pathogenicity (variants of unknown significance, VUS). This genetic uncertainty leads to three fundamental problems: (i) for IRD patients with multiple unclassified ABCA4 mutations, it is impossible to predict which variant will cause disease in relatives who have not yet developed it; (ii) development of variant-specific therapies remains limited; and (iii) these variants cannot be used to predict disease prospectively, which is essential for life-planning decisions and for directing patients to new clinical trials. This chapter describes approaches to deciphering the impact of ABCA4 genetic variants of unknown significance (VUS) using a combination of in silico and in vitro analyses. By leveraging complementary fields—protein biochemistry and computational biology—to create a “sequence-structure-function” workflow, where in silico 3D protein structural analysis of ABCA4 sequence variants serves as a tool to predict disease severity and clinical pathogenicity in conjunction with first-line bioinformatic tools and functional analysis. This approach represents a helpful step forward in understanding how ABCA4 variants affect structure and function and in evaluating their potential to cause inherited retinal diseases. © 2025
dc.description.sponsorshipUniversity of Delaware, UD; Foundation Fighting Blindness, FFB, (BR-GE-0623-0860-UDEL); Foundation Fighting Blindness, FFB; National Eye Institute, NEI, (R01EY036065); National Eye Institute, NEI
dc.identifier.doi10.1016/bs.apcsb.2024.12.003
dc.identifier.endpage460
dc.identifier.isbn9780443294143
dc.identifier.isbn9780443193507
dc.identifier.isbn9780323853170
dc.identifier.isbn9780128139165
dc.identifier.isbn9780323988957
dc.identifier.isbn9780124105232
dc.identifier.isbn9780128155615
dc.identifier.isbn9780443294105
dc.identifier.isbn9780323992299
dc.identifier.isbn9780128168448
dc.identifier.issn1876-1623
dc.identifier.pmid40973409
dc.identifier.scopus2-s2.0-105007036285
dc.identifier.scopusqualityQ2
dc.identifier.startpage423
dc.identifier.urihttps://doi.org/10.1016/bs.apcsb.2024.12.003
dc.identifier.urihttps://hdl.handle.net/20.500.12868/4611
dc.identifier.volume147
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherAcademic Press Inc.
dc.relation.ispartofAdvances in Protein Chemistry and Structural Biology
dc.relation.publicationcategoryKitap Bölümü - Uluslararası
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.snmzKA_Scopus_20260121
dc.subjectABC transporter
dc.subjectABCA4
dc.subjectATPase
dc.subjectBioinformatics
dc.subjectGenetic variants
dc.subjectInherited retinal degeneration
dc.subjectProtein structure computational modeling
dc.subjectVariants of unknown significance
dc.subjectVirus-like particle
dc.subjectVisual disease
dc.titleDeciphering the impact of ABCA4 genetic variants of unknown significance in inherited retinal disease through computational and functional approaches
dc.typeBook Chapter

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