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.

RESUMORaquitismo e osteomalacia são defeitos da mineralização óssea. O raquitismo é caracterizado por anormalidades na formação na placa epifisária de crescimento, com áreas não mineralizadas, desorganização da arquitetura celular e retardo na maturação óssea. A osteomalacia é caracterizada pela deficiente mineralização da matriz osteóide do osso cortical e trabecular com acúmulo do tecido osteóide pouco mineralizado. São processos que, em geral, ocorrem associados. Após o final do crescimento, com o fechamento da cartilagem epifisária, apenas a osteomalacia permanece. A falha do processo de mineralização tem como uma das principais causas a inadequada concentração extracelular de cálcio e fósforo, os dois principais componentes minerais do osso, e a falta ou comprometimento da ação dos elementos responsáveis pela sua absorção, particularmente a vitamina D. As principais manifestações clínicas como as deformidades ósseas e o atraso no crescimento, são semelhantes nos diferentes tipos de raquitismo e osteomalacia existem características que são específicas. As causas são adquiridas ou hereditárias e os recentes avanços em biologia molecular permitem a identificação dos genes envolvidos e das mutações. Essa discussão inclui os principais tipos da patologia. (Arq Bras Endocrinol Metab 1999; 43/6: 457-466) Unitermos: Raquitismo; Osteomalacia; Vitamina D; Hipofosfatemia ABSTRACT Rickets and osteomalacia are bone mineralization disorders. Rickets in children occurs due to abnormalities in bone formation at the epiphyseal growth plate and results in defective bone modelling. The growth plate is involved in a process characterized by defective calcification of cartilage, delayed maturation and disorganization of the architecture of the cartilage cells. In osteomalacia there is a failure to mineralize the osteoid organic matrix of bone. This defect results in excessive accumulation of osteoid throughout the skeleton. There is usually some decrease in bone density. Therefore, rickets occurs during growth in children and osteomalacia presents in adults. The mineralization of bone depends on availability and appropriate regulation of inorganic phosphate and calcium, that is made by vitamin D. The two components form a major part of hydroxyapatite, the mineral part of bone. Depletion of phosphate or calcium with abnormally low concentrations in extracellular fluid, results in rickets and osteomalacia. Although the clinical manifestations vary to some extend depending upon the underlying disorder, they are mainly related to skeletal deformity, and disturbances in growth. A number of different hereditary or acquired disorders are associated with the mechanism of defective mineralization. Recent advances in molecular genetics are permitting the identification of genes involved in human diseases from their chromossomal location. The ensuing discussion includes major types of rickets and osteomalacia. (Arq Bras Endocrinol Metab 1999; 43/6: 457-466)