title: A novel nonsense mutation in the first zinc finger of the vitamin D receptor causing hereditary 1,25-dihydroxyvitamin D3-resistant rickets.
abstract: 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.
authors.affiliation: Division of Endocrinology, Hospital das Clínicas, University of Sao Paulo, Brazil.
authors.forename: J B
authors.initials: JB
authors.lastname: Mechica
authors.forename: M O
authors.initials: MO
authors.lastname: Leite
authors.forename: B B
authors.initials: BB
authors.lastname: Mendonca
authors.forename: E S
authors.initials: ES
authors.lastname: Frazzatto
authors.forename: A
authors.initials: A
authors.lastname: Borelli
authors.forename: A C
authors.initials: AC
authors.lastname: Latronico
mesh_terms: D001120:Arginine / Q000235:genetics; D001483:Base Sequence; D002117:Calcitriol / Q000097:blood; D002648:Child; D003062:Codon; D018076:DNA, Complementary / Q000737:chemistry; D006801:Humans; D007015:Hypophosphatemia, Familial / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000235:genetics*; D016335:Zinc Fingers
chemical_list: D003062:Codon; D018076:DNA, Complementary; D018167:Receptors, Calcitriol; D001120:Arginine; D002117:Calcitriol