Vitamin D receptor mutations in patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets

Context: Hereditary vitamin D resistant rickets (HVDRR), also known as vitamin D-dependent rickets type II, is an autosomal recessive disorder characterized by the early onset of rickets with hypocalcemia, secondary hyperparathyroidism and hypophosphatemia and is caused by mutations in the vitamin D receptor (VDR) gene. The human gene encoding the VDR is located on chromosome 12 and comprises eight coding exons and seven introns. Objectives, patients, and methods: We analyzed the VDR gene of 5 previously unreported patients, two from Singapore and one each from Macedonia (former Yugoslav Republic), Saudi Arabia and Turkey. Each patient had clinical and radiographic features of rickets, hypocalcemia, and the 4 cases that had the measurement showed elevated serum concentrations of 1,25-dihydroxyvitamin D (1,25(OH)₂D). Mutations were re-created in the WT VDR cDNA and examined for 1,25(OH)₂D₃-mediated transactivation in COS-7 monkey kidney cells. Results: Direct sequencing identified four novel mutations and two previously described mutations in the VDR gene. The novel mutations included a missense mutation in exon 3 causing the amino acid change C60W; a missense mutation in exon 4 causing the amino acid change D144N; a missense mutation in exon 7 causing the amino acid change N276Y; and a 2. bp deletion in exon 3 5'-splice site (IVS3+4-5) leading to a premature stop. Conclusions: These 4 unique mutations add to the previous 45 mutations identified in the VDR gene in patients with HVDRR.