{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T16:03:44Z","timestamp":1788537824362,"version":"build-2803163510"},"reference-count":69,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T00:00:00Z","timestamp":1638316800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL131690"],"award-info":[{"award-number":["HL131690"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:p>\n                    UbiA prenyltransferase domain\u2010containing protein\u20101 (UBIAD1) is responsible for the biosynthesis of menaquinone\u20104 (MK\u20104), a cofactor for extrahepatic carboxylation of vitamin K\u2010dependent (VKD) proteins. Genetic variations of UBIAD1 are mainly associated with Schnyder corneal dystrophy (SCD), a disease characterized by abnormal accumulation of cholesterol in the cornea. Results from\n                    <jats:italic>in\u2009vitro<\/jats:italic>\n                    studies demonstrate that SCD\u2010associated UBIAD1 mutations are defective in MK\u20104 biosynthesis. However, SCD patients do not exhibit typical phenotypes associated with defects of MK\u20104 or VKD carboxylation. Here, we coupled UBIAD1\u2019s biosynthetic activity of MK\u20104 with VKD carboxylation in HEK293 cells that stably express a chimeric VKD reporter protein. The endogenous\n                    <jats:italic>Ubiad1<\/jats:italic>\n                    gene in these cells was knocked out by CRISPR\u2010Cas9\u2010mediated genome editing. The effect of UBIAD1 mutations on MK\u20104 biosynthesis and VKD carboxylation was evaluated in\n                    <jats:italic>Ubiad1<\/jats:italic>\n                    \u2010deficient reporter cells by determining the production of MK\u20104 or by measuring the efficiency of reporter\u2010protein carboxylation. Our results show that the hot\u2010spot mutation N102S has a moderate impact on MK\u20104 biosynthesis (retained \u02dc\u200982% activity) but does not affect VKD carboxylation. However, the G186R mutation significantly affected both MK\u20104 biosynthesis and VKD carboxylation. Other mutations exhibit varying degrees of effects on MK\u20104 biosynthesis and VKD carboxylation. These results are consistent with\n                    <jats:italic>in\u2009vivo<\/jats:italic>\n                    results obtained from gene knock\u2010in mice and SCD patients. Our findings suggest that UBIAD1\u2019s MK\u20104 biosynthetic activity does not directly correlate with the phenotypes of SCD patients. The established cell\u2010based assays in this study provide a powerful tool for the functional studies of UBIAD1 in a cellular milieu.\n                  <\/jats:p>","DOI":"10.1111\/febs.16291","type":"journal-article","created":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T19:33:27Z","timestamp":1637696007000},"page":"2613-2627","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Naturally occurring UBIAD1 mutations differentially affect menaquinone biosynthesis and vitamin K\u2010dependent carboxylation"],"prefix":"10.1111","volume":"289","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8459-2557","authenticated-orcid":false,"given":"Xuejie","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Biology University of North Carolina at Chapel Hill  NC 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