{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T19:16:14Z","timestamp":1785784574346,"version":"3.56.0"},"reference-count":30,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T00:00:00Z","timestamp":1738108800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Alkaptonuria (AKU) is a rare metabolic disorder characterized by the accumulation of homogentisic acid (HGA), leading to progressive ochronosis and joint degeneration. While much is known about HGA\u2019s role in tissue damage, the molecular mechanisms underlying acute inflammation in AKU remain poorly understood. Serum amyloid A (SAA) proteins are key mediators of the inflammatory response, yet their potential as biomarkers for inflammation in AKU has not been explored. This study investigated the role of the SAA1.1 allele as a biomarker for the severity of acute inflammation in AKU. Data from the ApreciseKUre Precision Medicine Ecosystem were analyzed to assess the relationship between SAA1 allelic variants and inflammatory markers. Molecular dynamics simulations compared the structural dynamics of SAA1.1 and SAA1.2 isoforms, with standard modeling and analysis pipelines employed. Using a clinomics approach, we showed that AKU patients expressing the SAA1.1 allele have significantly higher acute inflammation-related markers. Extensive molecular dynamics simulations revealed that the SAA1.1 isoform lent high structural instability of the C-terminal domain, accelerating the formation of amyloid fibrils and exacerbating the inflammatory condition. These findings would identify the SAA1.1 allele as a novel genetic biomarker for the progression of secondary amyloidosis in AKU and its severity. Furthermore, new molecular insights into the inflammatory mechanisms of AKU were provided, suggesting potential therapeutic approaches aimed at stabilizing SAA1.1 protein and preventing amyloid fibril formation, with significant implications in AKU and precision medicine strategies for SAA-related diseases.<\/jats:p>","DOI":"10.3390\/biom15020194","type":"journal-article","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T10:36:28Z","timestamp":1738146988000},"page":"194","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Integrated Clinomics and Molecular Dynamics Simulation Approaches Reveal the SAA1.1 Allele as a Biomarker in Alkaptonuria Disease Severity"],"prefix":"10.3390","volume":"15","author":[{"given":"Alfonso","family":"Trezza","sequence":"first","affiliation":[{"name":"ONE-HEALTH Laboratory, Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0009-4011","authenticated-orcid":false,"given":"Bianca","family":"Roncaglia","sequence":"additional","affiliation":[{"name":"ONE-HEALTH Laboratory, Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9281-034X","authenticated-orcid":false,"given":"Anna","family":"Visibelli","sequence":"additional","affiliation":[{"name":"ONE-HEALTH Laboratory, Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2750-7082","authenticated-orcid":false,"given":"Roberta","family":"Barletta","sequence":"additional","affiliation":[{"name":"ONE-HEALTH Laboratory, Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4924-5423","authenticated-orcid":false,"given":"Luana","family":"Peruzzi","sequence":"additional","affiliation":[{"name":"ONE-HEALTH Laboratory, Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Marzocchi","sequence":"additional","affiliation":[{"name":"ONE-HEALTH Laboratory, Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9657-4169","authenticated-orcid":false,"given":"Daniela","family":"Braconi","sequence":"additional","affiliation":[{"name":"ONE-HEALTH Laboratory, Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0263-7107","authenticated-orcid":false,"given":"Ottavia","family":"Spiga","sequence":"additional","affiliation":[{"name":"ONE-HEALTH Laboratory, Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6976-9086","authenticated-orcid":false,"given":"Annalisa","family":"Santucci","sequence":"additional","affiliation":[{"name":"ONE-HEALTH Laboratory, Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 53100 Siena, Italy"},{"name":"MetabERN, Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 53100 Siena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101123","DOI":"10.1016\/j.isci.2020.101123","article-title":"Rare Genetic Diseases: Nature\u2019s Experiments on Human Development","volume":"23","author":"Lee","year":"2020","journal-title":"iScience"},{"key":"ref_2","first-page":"3","article-title":"Analysis of HGD Gene Mutations in Patients with Alkaptonuria from the United Kingdom: Identification of Novel Mutations","volume":"24","author":"Usher","year":"2015","journal-title":"JIMD Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.ijscr.2014.06.015","article-title":"A rare cause of arthropathy: An ochronotic patient with black joints","volume":"5","author":"Harun","year":"2014","journal-title":"Int. J. Surg. Case Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/0006-291X(86)90352-9","article-title":"Localization of Human SAA Gene(s) to Chromosome 11 and Detection of DNA Polymorphisms","volume":"137","author":"Naylor","year":"1986","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sori\u0107 Hosman, I., Kos, I., and Lamot, L. (2021). Serum Amyloid A in Inflammatory Rheumatic Diseases: A Compendious Review of a Renowned Biomarker. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.631299"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1136\/ard.60.2.124","article-title":"Relative Serum Amyloid A (SAA) Values: The Influence of SAA1 Genotypes and Corticosteroid Treatment in Japanese Patients with Rheumatoid Arthritis","volume":"60","author":"Yamada","year":"2001","journal-title":"Ann. Rheum. Dis."},{"key":"ref_7","first-page":"793628","article-title":"Serum Amyloid A as a Marker of Persistent Inflammation and an Indicator of Cardiovascular and Renal Involvement in Patients with Rheumatoid Arthritis","volume":"2014","author":"Majdan","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s11883-020-00901-4","article-title":"High-Density Lipoproteins and Serum Amyloid A (SAA)","volume":"23","author":"Webb","year":"2021","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"16115","DOI":"10.1073\/pnas.1306621110","article-title":"Pathogenetic Mechanisms of Amyloid A Amyloidosis","volume":"110","author":"Simons","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.gene.2016.02.044","article-title":"Serum Amyloid A1: Structure, Function, and Gene Polymorphism","volume":"583","author":"Sun","year":"2016","journal-title":"Gene"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5189","DOI":"10.1073\/pnas.1322357111","article-title":"Structural Mechanism of Serum Amyloid A-Mediated Inflammatory Amyloidosis","volume":"111","author":"Lu","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.2174\/0929867323666160418114600","article-title":"Structure and Expression of Different Serum Amyloid A (SAA) Variants and Their Concentration-Dependent Functions During Host Insults","volume":"23","author":"Gouwy","year":"2016","journal-title":"Curr. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"67","DOI":"10.3109\/13506129908993291","article-title":"Revised Nomenclature for Serum Amyloid A (SAA)","volume":"6","author":"Sipe","year":"1999","journal-title":"Amyloid"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1093\/rheumatology\/ken371","article-title":"Increased Susceptibility of Serum Amyloid A 1.1 to Degradation by MMP-1: Potential Explanation for Higher Risk of Type AA Amyloidosis","volume":"47","author":"Yamada","year":"2008","journal-title":"Rheumatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.kint.2021.09.007","article-title":"A Mutation in the SAA1 Promoter Causes Hereditary Amyloid A Amyloidosis","volume":"101","author":"Sikora","year":"2022","journal-title":"Kidney Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1007\/s10545-015-9842-8","article-title":"Amyloidosis in Alkaptonuria","volume":"38","author":"Millucci","year":"2015","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Mastroeni, P., Trezza, A., Geminiani, M., Frusciante, L., Visibelli, A., and Santucci, A. (2024). HGA Triggers SAA Aggregation and Accelerates Fibril Formation in the C20\/A4 Alkaptonuria Cell Model. Cells, 13.","DOI":"10.3390\/cells13171501"},{"key":"ref_18","first-page":"72","article-title":"MEFV and SAA1 Genotype Associations with Clinical Features of Familial Mediterranean Fever and Amyloidosis in Armenia","volume":"34","author":"Atoyan","year":"2016","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Visibelli, A., Cicaloni, V., Spiga, O., and Santucci, A. (2022). Computational Approaches Integrated in a Digital Ecosystem Platform for a Rare Disease. Front. Mol. Med., 2.","DOI":"10.3389\/fmmed.2022.827340"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e053674","DOI":"10.1136\/bmjopen-2021-053674","article-title":"Biomarker discovery studies for patient stratification using machine learning analysis of omics data: A scoping review","volume":"11","author":"Glaab","year":"2021","journal-title":"BMJ Open"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Visibelli, A., Roncaglia, B., Spiga, O., and Santucci, A. (2023). The Impact of Artificial Intelligence in the Odyssey of Rare Diseases. Biomedicines, 11.","DOI":"10.3390\/biomedicines11030887"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"D941","DOI":"10.1093\/nar\/gky1015","article-title":"COSMIC: The Catalogue of Somatic Mutations in Cancer","volume":"47","author":"Tate","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_23","unstructured":"UniProt Consortium (2023). UniProt: The Universal Protein Knowledgebase in 2023. Nucleic Acids Res., 51, D523\u2013D531."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1093\/bioinformatics\/btaa849","article-title":"PyMod 3: A Complete Suite for Structural Bioinformatics in PyMOL","volume":"37","author":"Janson","year":"2021","journal-title":"Bioinformatics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1107\/S0021889892009944","article-title":"PROCHECK: A Program to Check the Stereochemical Quality of Protein Structures","volume":"26","author":"Laskowski","year":"1993","journal-title":"J. Appl. Crystallogr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A Web-Based Graphical User Interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"GROMACS: Fast, Flexible, and Free","volume":"26","author":"Lindahl","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"W314","DOI":"10.1093\/nar\/gku411","article-title":"DUET: A Server for Predicting Effects of Mutations on Protein Stability Using an Integrated Computational Approach","volume":"42","author":"Pires","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2695","DOI":"10.1093\/bioinformatics\/btl461","article-title":"Bio3D: An R Package for the Comparative Analysis of Protein Structures","volume":"22","author":"Grant","year":"2006","journal-title":"Bioinformatics"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/2\/194\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:38:25Z","timestamp":1759919905000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/2\/194"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,29]]},"references-count":30,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["biom15020194"],"URL":"https:\/\/doi.org\/10.3390\/biom15020194","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,29]]}}}