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Vitamin D 1-Hydroxylase Gene Mutations in Patients with 1-Hydroxylase Deficiency

Department of Pediatrics (C.J.K., L.E.K., F.P., N.H., W.L.M., A.A.P.), University of California, San Francisco, San Francisco, California 94143; Pediatric Nephrology (A.S.), MassGeneral Hospital for Children, Massachusetts General Hospital and Harvard School of Medicine, Boston, Massachusetts 02114; and Department of Pediatrics (Y.C.), Seoul National University Children’s Hospital, Seoul 110-744, Korea

Address all correspondence and requests for reprints to: Anthony A. Portale, M.D., University of California, San Francisco, 533 Parnassus Avenue, Box 0748, Room U-585, San Francisco, California 94143-0748. E-mail: aportale{at}peds.ucsf.edu.

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 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, and Methods: We analyzed the 1-hydroxylase gene of 10 patients, five from Korea, two from the United States, 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.

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 (2561GA) 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 (1031CT) 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 GA) 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.