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

Steroid hormones are central regulators of a variety of biological processe s. According to the free hormone hypothesis, steroids enter target cells by passive diffusion. However, recently we demonstrated that 25(OH) vitamin D -3 complexed to its plasma carrier, the vitamin D-binding protein, enters r enal proximal tubules by receptor-mediated endocytosis. Knockout mice lacki ng the endocytic receptor megalin lose 25(OH) vitamin D-3 in the urine and develop bone disease. Here, we report that cubilin, a membrane-associated p rotein colocalizing with megalin, facilitates the endocytic process by sequ estering steroid-carrier complexes on the cellular surface before megalin-m ediated internalization of the cubilin-bound ligand. Dogs with an inherited disorder affecting cubilin biosynthesis exhibit abnormal vitamin D metabol ism. Similarly, human patients with mutations causing cubilin dysfunction e xhibit urinary excretion of 25(OH) vitamin D-3. This observation identifies spontaneous mutations in an endocytic receptor pathway affecting cellular uptake and metabolism of a steroid hormone.