{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T02:59:47Z","timestamp":1776135587896,"version":"3.50.1"},"reference-count":57,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,6,7]],"date-time":"2025-06-07T00:00:00Z","timestamp":1749254400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Proteomics Clinical Apps"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>The human retina relies on a complex network of proteins, many of which exhibit intrinsic disorder and liquid\u2010liquid phase separation (LLPS), enabling dynamic interactions for retinal function. Disruptions in these properties, along with missense mutations, have been linked to retinal diseases. This study aims to characterize and compare retinal proteins categorized by their expression specificity and tissue distribution using bioinformatics tools to explore relationships between intrinsic protein disorder, phase separation potential, and mutation pathogenicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed retinal proteins classified by the Human Protein Atlas (HPA) into two major groups based on gene expression <jats:italic>specificity<\/jats:italic> (degree of unique retinal expression) and gene expression <jats:italic>distribution<\/jats:italic> (extent of expression across tissues). We analyzed nine retinal proteomes categorized by gene expression <jats:italic>specificity<\/jats:italic> and <jats:italic>distribution<\/jats:italic>. Intrinsic protein disorder was assessed using per\u2010residue and global disorder predictors from the Rapid Intrinsic Disorder Analysis Online (RIDAO) platform, LLPS potential was evaluated with ParSe v2, and missense mutation pathogenicity was predicted using AlphaMissense.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Significant differences in per\u2010residue intrinsic protein disorder were found within the <jats:italic>specificity<\/jats:italic> and <jats:italic>distribution<\/jats:italic> subgroups (<jats:italic>p<\/jats:italic> &lt; 0.0001). In addition, global disorder predictions from the RIDAO platform demonstrated non\u2010random distributions of protein species across the proteomes analyzed in both subgroups (<jats:italic>p<\/jats:italic> &lt; 0.0001). Furthermore, proteins specifically elevated in the retina exhibited higher intrinsic disorder and greater phase separation propensity (ParSe v2, AUC up to 0.650), compared to those more broadly expressed. Lastly, AlphaMissense analysis showed significant variations in the average pathogenicity scores of missense mutations within subgroups (<jats:italic>p<\/jats:italic> &lt; 0.0001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results show that intrinsic disorder, LLPS, and mutational tendencies are not evenly distributed among retinal proteomes. Our study demonstrates a link between intrinsic disorder, LLPS potential, and pathogenic vulnerability among retinal proteins, underscoring the unique structural and functional landscape of retinal proteomes. Proteins with higher specificity to the retina exhibit greater disorder and phase separation potential, highlighting their potential role in dynamic cellular processes that support retinal function. Conversely, proteins widely distributed across multiple tissues tend to be more ordered, suggesting a need for structural stability in their broader functional roles.<\/jats:p><\/jats:sec>","DOI":"10.1002\/prca.70012","type":"journal-article","created":{"date-parts":[[2025,6,7]],"date-time":"2025-06-07T06:14:28Z","timestamp":1749276868000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Bioinformatics\u2010Based Comparative Analysis of the Human Retina Proteome"],"prefix":"10.1002","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3729-413X","authenticated-orcid":false,"given":"Colin K.","family":"Kim","sequence":"first","affiliation":[{"name":"Bascom Palmer Eye Institute University of Miami Miami Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mak B.","family":"Djulbegovic","sequence":"additional","affiliation":[{"name":"Wills Eye Hospital Thomas Jefferson University Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Broytman","sequence":"additional","affiliation":[{"name":"Cooper Medical School of Rowan University Camden New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nedym","family":"Hadzijahic","sequence":"additional","affiliation":[{"name":"Bascom Palmer Eye Institute University of Miami Miami Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Antonietti","sequence":"additional","affiliation":[{"name":"Bascom Palmer Eye Institute University of Miami Miami Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J. 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