Human 25-hydroxyvitamin D-1alpha-hydroxylase: cloning, mutations, and gene expression.

The rate-limiting, hormonally regulated step in the bioactivation of vitamin D is the 1alpha-hydroxylation of 25-hydroxyvitamin D, which occurs in the kidney and other tissues and is catalyzed by the mitochondrial cytochrome P450 enzyme, P450c1alpha. After many years of effort, the cDNA and gene encoding this enzyme were cloned from mouse, rat, and human tissue in late 1997. The human gene encoding the 1alpha-hydroxylase is 5 kb in length, located on chromosome 12, and comprises nine exons and eight introns; its intron/exon organization is very similar to that of the other four mitochondrial P450 enzymes cloned to date. Mutations in P450c1alpha cause 1alpha-hydroxylase deficiency, also known as vitamin D-dependent rickets type 1, a rare autosomal recessive disease characterized by rickets and impaired growth due to failure of renal synthesis of 1,25(OH)2D. To date, 31 patients have been studied and 20 distinct mutations in the gene identified, including 13 mis-sense mutations, none of which encode a protein with significant enzyme activity. Recent studies in animals demonstrate that regulation of P450c1alpha gene expression by parathyroid hormone (PTH), low calcium diet, low phosphorus diet, and 1,25(OH)2D occurs at the level of its mRNA. Transcriptional activity of the mouse and human P450c1alpha gene promoters can be stimulated by PTH, cAMP, and forskolin and suppressed by 1,25(OH)2D.