A Novel Nonsense Mutation in the First Zinc Finger of the Vitamin D Receptor Causing Hereditary 1,25-Dihydroxyvitamin D3-Resistant Rickets

Hereditary 1,25-dihydroxyvitamin D3[ 1,25-(OH)2D3]-resistant rickets (HVDRR) is a rare autosomal recessive disorder resulting in target organ resistance to the active form of vitamin D[ 1,25-(OH)2D3]. Point mutations in the vitamin D receptor (VDR) gene have been identified in HVDRR. We investigated the molecular basis of HVDRR in a Brazilian family with two affected siblings. The propositus is a 12-yr-old boy born to first cousin parents who exhibited the classical pattern of the HVDRR, including early-onset rickets, total alopecia, convulsions, hypocalcemia, secondary hyperparathyroidism, and elevated 1,25-(OH)2D3 serum levels. His younger sister also developed clinical and biochemical features of HVDRR at 1 month of age and died at 4 yr of age. Genomic DNA was isolated from peripheral blood of the boy and from dried umbilical cord tissue of his affected sister. We amplified exons 2 and 3 of the VDR gene, which encode the zinc finger DNA-binding domain by PCR. Direct sequencing of the PCR products revea...