{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T14:31:16Z","timestamp":1790260276523,"version":"4.1.0"},"reference-count":40,"publisher":"The Endocrine Society","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Context:<\/jats:title><jats:p>CYP27B1 converts 25-hydroxyvitamin D3 to active 1,25-dihydroxyvitamin D3, playing a vital role in calcium homeostasis and bone growth. Vitamin D-dependent rickets type 1 (VDDR-1) is a rare autosomal recessive disorder caused by mutations in CYP27B1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective:<\/jats:title><jats:p>The objective of the study was an enzymatic and structural analysis of mutations in a patient with calcipenic rickets.<\/jats:p><\/jats:sec><jats:sec><jats:title>Design, Setting, Patient, and Intervention:<\/jats:title><jats:p>Two siblings presented with calcipenic rickets and normal 1,25-dihydroxyvitamin D3 levels. CYP27B1 gene analysis showed compound heterozygous mutations confirming VDDR-1. We studied wild-type CYP27B1 and mutations H441Y and R459L by computational homology modeling, molecular dynamics simulations, and functional studies using a luciferase assay. The patients were successfully treated with calcitriol.<\/jats:p><\/jats:sec><jats:sec><jats:title>Main Outcome:<\/jats:title><jats:p>The main outcomes of the study were novel mutations leading to a severe loss of CYP27B1 activities for metabolism of 25-hydroxyvitamin D3.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results:<\/jats:title><jats:p>Mitochondrial cytochrome P450s require adrenodoxin (FDX1) and adrenodoxin reductase. We created models of CYP27B1-FDX1 complex, which revealed negative effects of mutations H441Y and R459L. Upon structural analysis, near-identical folds, protein contact areas, and orientations of heme\/iron-sulfur cluster suggested that both mutations may destabilize the CYP27B1-FDX1 complex by negating directional interactions with adrenodoxin. This system is highly sensitive to small local changes modulating the binding\/dissociation of adrenodoxin, and electron-transporting efficiency might change with mutations at the surface. Functional assays confirmed this hypothesis and showed severe loss of activity of CYP27B1 by both mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions:<\/jats:title><jats:p>This is the first report of mutations in CYP27B1 causing VDDR-1 by affecting protein-protein interactions with FDX1 that results in reduced CYP27B1 activities. Detailed characterization of mutations in CYP27B1 is required for understanding the novel molecular mechanisms causing VDDR-1.<\/jats:p><\/jats:sec>","DOI":"10.1210\/jc.2016-2124","type":"journal-article","created":{"date-parts":[[2016,7,11]],"date-time":"2016-07-11T17:02:11Z","timestamp":1468256531000},"page":"3409-3418","source":"Crossref","is-referenced-by-count":41,"title":["Vitamin D-Dependent Rickets Type 1 Caused by Mutations in CYP27B1 Affecting Protein Interactions With Adrenodoxin"],"prefix":"10.1210","volume":"101","author":[{"given":"Adam","family":"Zalewski","sequence":"first","affiliation":[{"name":"Division of Pediatric Endocrinology, Diabetology, and Metabolism (A.Z., B.L., C.E.F., A.V.P.), Department of Pediatrics, University Children's Hospital, Inselspital, Bern, and Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina 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