Context: Vitamin D 1-hydroxylase deficiency, also known as vitamin D-dependent rickets type 1, is an autosomal recessive disorder characterized by the early onset of rickets with hypocalcemia and is caused by mutations of the 25-hydroxyvitamin D 1-hydroxylase (1-hydroxylase, CYP27B1) gene. The human gene encoding the 1-hydroxylase is 5 kb in length, located on chromosome on 12, and comprises nine exons and eight introns. We previously isolated the human 1-hydroxylase cDNA and gene and identified 19 different mutations in 25 patients with 1-hydroxylase deficiency.

Objectives, Patients, Methods: We analyzed the 1-hydroxylase gene of ten patients, 5 from Korea, 2 from the USA, and one each from Argentina, Denmark, and Morocco, all from nonconsanguineous families. Each had clinical and radiographic features of rickets, hypocalcemia, and low serum concentrations of 1, 25-dihydroxyvitamin D₃ [1,25(OH)₂D].

Results: Direct sequencing identified the responsible 1-hydroxylase gene mutations in 19 of 20 alleles. Four novel and four known mutations were identified. The new mutations included: a nonsense mutation in exon 6, substitution of adenine for guanine (2561G>A) creating a stop signal at codon 328; deletion of adenine in exon 9 (3922delA) causing a frameshift; substitution of thymine for cytosine in exon 2 (1031C>T) causing the amino acid change P112L; and a splice site mutation, substitution of adenine for guanine in the first nucleotide of intron 7 (IVS7+1 G>A) causing a frameshift.

Conclusions: Mutations in the 1-hydroxylase gene previously were identified in 44 patients, to which we add 10 more. The studies show a strong correlation between 1-hydroxylase mutations and the clinical findings of 1-hydroxylase deficiency.