Vitamin D Receptor Mutations in Patients with Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets

Abstract 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) 2 D). Mutations were re-created in the WT VDR cDNA and examined for 1,25(OH) 2 D 3 -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 2bp 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.