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Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D-3

Item Type:Article
Title:Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D-3
Creators Name:Nykjaer, A. and Fyfe, J.C. and Kozyraki, R. and Leheste, J.R. and Jacobsen, C. and Nielsen, M.S. and Verroust, P.J. and Aminoff, M. and de la Chapelle, A. and Moestrup, S.K. and Ray, R. and Gliemann, J. and Willnow, T.E. and Christensen, E.I.
Abstract:Steroid hormones are central regulators of a variety of biological processes. According to the free hormone hypothesis, steroids enter target cells by passive diffusion. However, recently we demonstrated that 25(OH) vitamin D3 complexed to its plasma carrier, the vitamin D-binding protein, enters renal proximal tubules by receptor-mediated endocytosis. Knockout mice lacking the endocytic receptor megalin lose 25(OH) vitamin D3 in the urine and develop bone disease. Here, we report that cubilin, a membrane-associated protein colocalizing with megalin, facilitates the endocytic process by sequestering steroid-carrier complexes on the cellular surface before megalin-mediated internalization of the cubilin-bound ligand. Dogs with an inherited disorder affecting cubilin biosynthesis exhibit abnormal vitamin D metabolism. Similarly, human patients with mutations causing cubilin dysfunction exhibit urinary excretion of 25(OH) vitamin D3. This observation identifies spontaneous mutations in an endocytic receptor pathway affecting cellular uptake and metabolism of a steroid hormone.
Keywords:Calcifediol, Cell Surface Receptors, Hormones, LDL-Receptor Related Protein 2, Mutation, Vitamin D-Binding Protein, Animals, Dogs, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:98
Number:24
Page Range:13895-13900
Date:1 January 2001
Official Publication:https://doi.org/10.1073/pnas.241516998
PubMed:View item in PubMed

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