Editors' ChoiceMolecular Endocrinology

Too Much of a Good Thing

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Science Translational Medicine  17 Aug 2011:
Vol. 3, Issue 96, pp. 96ec132
DOI: 10.1126/scitranslmed.3003034

Rickets and osteomalacia, which result in softening of the bones from lack of vitamin D, can be caused by either dietary vitamin D deficiency or mutations in the vitamin D receptor. These maladies have largely been controlled by widespread use of calcium and vitamin D supplementation in public health. However, incidence of idiopathic infantile hypercalcemia—a rare pediatric autosomal recessive disorder characterized by too much calcium in the blood and kidneys, failure to thrive, vomiting, and dehydration—has increased in England during this period of high vitamin D supplementation. Now, in an elegant genomic study using a candidate-gene approach, Schlingmann et al. identify the molecular underpinning of this disease.

Schlingmann et al. evaluated six infants from four families with idiopathic infantile hypercalcemia and used their peripheral blood cells to identify defective genes in the vitamin D metabolic pathway. They identified both homozygous and compound heterozygous mutations in the gene encoding the vitamin D–metabolizing enzyme CYP24A1. Similar mutations were also identified in a second cohort of four children who developed severe hypercalcemia after a single high dose of oral vitamin D supplementation, which is presumably a milder version of idiopathic infantile hypercalcemia. Most importantly, the authors found that most of these mutations resulted in complete loss of CYP24A1 function when expressed in cell culture models and subsequently diminished or decreased metabolism of vitamin D products. The phenotypes of these mutations bear striking similarity to a mouse knockout model of CYP24A1. Protein structural analysis indicated that these mutations probably affect critical regions of the protein that are important for its folding, enzymatic activity, or substrate binding, therefore resulting in loss of function.

These results demonstrate a causative role of CYP24A1 in the molecular pathogenesis of idiopathic infantile hypercalcemia and add to the growing list of components of the vitamin D signaling pathway implicated in human diseases. These studies not only indicate caution for general prophylactic vitamin D administration, they also provide an attractive druggable enzymatic target for perhaps much larger populations of patients with vitamin D deficiency, such as the elderly.

K. P. Schlingmann et al., Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N. Engl. J. Med. 365, 410–421 (2011). [Abstract]

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