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

Division of Endocrinology, Hospital das Clínicas, University of Sao Paulo, Sao Paulo, Brazil

Address all correspondence and requests for reprints to: Dr. Ana C. Latronico, Divisão de Endocrinologia, Hospital das Clínicas da Universidade de Sao Paulo, Caixa Postal 3671, CEP: 01060–970, Sao Paulo, Brazil.

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 revealed a homozygous substitution of cytosine for thymine at nucleotide position 88 in exon 2 of the VDR gene in both affected siblings. This point mutation determined the substitution of a stop codon (TGA) for arginine (CGA) at amino acid position 30 at the first zinc finger of the DNA-binding domain of the VDR. This substitution generated a truncated receptor missing 397 residues. The parents and a normal sister were heterozygous for this mutation. In conclusion, we describe a novel nonsense mutation in the first zinc finger of the VDR that generated a severely truncated form of this receptor.

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