Vitamin D-Dependent Rickets Type 1 Caused by Mutations in CYP27B1 Affecting Protein Interactions With Adrenodoxin.

Zalewski, Adam; Ma, Nina S; Legeza, Balazs; Renthal, Nora; Flück Pandey, Christa Emma; Pandey, Amit Vikram (2016). Vitamin D-Dependent Rickets Type 1 Caused by Mutations in CYP27B1 Affecting Protein Interactions With Adrenodoxin. The Journal of clinical endocrinology and metabolism, 101(9), pp. 3409-3418. Endocrine Society 10.1210/jc.2016-2124

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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.


The objective of the study was an enzymatic and structural analysis of mutations in a patient with calcipenic rickets. Design, Setting, Patient, and Intervention: 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.


The main outcomes of the study were novel mutations leading to a severe loss of CYP27B1 activities for metabolism of 25-hydroxyvitamin D3.


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.


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.

Item Type:

Journal Article (Further Contribution)


04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine > Endocrinology/Metabolic Disorders

UniBE Contributor:

Flück Pandey, Christa Emma, Pandey, Amit Vikram


600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology




Endocrine Society


[4] Swiss National Science Foundation


[102] Pathogenesis of disorders caused by human P450 oxidoreductase mutations Official URL




Amit Vikram Pandey

Date Deposited:

22 Sep 2016 09:55

Last Modified:

06 Jan 2023 18:57

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