{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T07:15:00Z","timestamp":1772262900688,"version":"3.50.1"},"reference-count":19,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T00:00:00Z","timestamp":1640217600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["PRIN project 2017483NH8"],"award-info":[{"award-number":["PRIN project 2017483NH8"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>MTHFR deficiency still deserves an investigation to associate the phenotype to protein structure variations. To this aim, considering the MTHFR wild type protein structure, with a catalytic and a regulatory domain and taking advantage of state-of-the-art computational tools, we explore the properties of 72 missense variations known to be disease associated. By computing the thermodynamic \u0394\u0394G change according to a consensus method that we recently introduced, we find that 61% of the disease-related variations destabilize the protein, are present both in the catalytic and regulatory domain and correspond to known biochemical deficiencies. The propensity of solvent accessible residues to be involved in protein-protein interaction sites indicates that most of the interacting residues are located in the regulatory domain, and that only three of them, located at the interface of the functional protein homodimer, are both disease-related and destabilizing. Finally, we compute the protein architecture with Hidden Markov Models, one from Pfam for the catalytic domain and the second computed in house for the regulatory domain. We show that patterns of disease-associated, physicochemical variation types, both in the catalytic and regulatory domains, are unique for the MTHFR deficiency when mapped into the protein architecture.<\/jats:p>","DOI":"10.3390\/ijms23010167","type":"journal-article","created":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T21:40:21Z","timestamp":1640295621000},"page":"167","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Glance into MTHFR Deficiency at a Molecular Level"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7359-0633","authenticated-orcid":false,"given":"Castrense","family":"Savojardo","sequence":"first","affiliation":[{"name":"Biocomputing Group, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9816-4737","authenticated-orcid":false,"given":"Giulia","family":"Babbi","sequence":"additional","affiliation":[{"name":"Biocomputing Group, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davide","family":"Baldazzi","sequence":"additional","affiliation":[{"name":"Biocomputing Group, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0274-5669","authenticated-orcid":false,"given":"Pier Luigi","family":"Martelli","sequence":"additional","affiliation":[{"name":"Biocomputing Group, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7462-7039","authenticated-orcid":false,"given":"Rita","family":"Casadio","sequence":"additional","affiliation":[{"name":"Biocomputing Group, Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy"},{"name":"Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), Italian National Research Council (CNR), 70126 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1002\/humu.22970","article-title":"Mutation Update and Review of Severe Methylenetetrahydrofolate Reductase Deficiency","volume":"37","author":"Froese","year":"2016","journal-title":"Hum. 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