Malloy Peter J, Zhu Wenjing, Bouillon Roger, Feldman David
Division of Endocrinology, Gerontology, and Metabolism, Department of Medicine, Stanford University School of Medicine, Stanford University Medical Center, Room S005, Stanford, CA 94305-5103, USA.
Mol Genet Metab. 2002 Dec;77(4):314-8. doi: 10.1016/s1096-7192(02)00173-7.
Hereditary 1,25-dihydroxyvitamin D resistant rickets (HVDRR) is a genetic disorder most often caused by mutations in the vitamin D receptor (VDR). In this report, we present our findings on a young girl who exhibited the typical clinical features of HVDRR with early onset rickets, hypocalcemia, secondary hyperparathyroidism, and elevated serum concentrations of alkaline phosphatase and 1,25-dihydroxyvitamin D [1,25(OH)(2)D(3)]. The patient also had total body alopecia. Fibroblasts from the patient were cultured for analysis of the VDR structure and function. In [3H]1,25(OH)(2)D(3) binding assays, no significant specific binding to the VDR was observed in cytosols from the patient's fibroblasts. The patient's fibroblast were also totally resistant to high doses of 1,25(OH)(2)D(3) as demonstrated by their failure to induce expression of the 24-hydroxylase gene, a marker of 1,25(OH)(2)D(3) activity. DNA sequence analysis of the VDR gene uncovered a unique C to T mutation in exon 8. The mutation changed the codon for glutamine to a premature stop codon at amino acid 317 (Q317X). Restriction enzyme analysis showed that the patient was homozygous for the mutation. Both parents were heterozygous for the mutant allele. In conclusion, we have identified a novel mutation in the VDR, Q317X, as the molecular defect in a patient with HVDRR. The Q317X mutation deletes 110 amino acids of the ligand-binding domain of the VDR and results in the loss of [3H]1,25(OH)(2)D(3) binding and target gene transactivation.
遗传性1,25 - 二羟维生素D抵抗性佝偻病（HVDRR）是一种遗传性疾病，最常见的病因是维生素D受体（VDR）的突变。在本报告中，我们展示了对一名年轻女孩的研究结果，该女孩表现出HVDRR的典型临床特征，包括早发性佝偻病、低钙血症、继发性甲状旁腺功能亢进以及血清碱性磷酸酶和1,25 - 二羟维生素D [1,25(OH)(2)D(3)]浓度升高。该患者还出现了全身脱发。培养患者的成纤维细胞以分析VDR的结构和功能。在[3H]1,25(OH)(2)D(3)结合试验中，在患者成纤维细胞的胞质溶胶中未观察到与VDR的显著特异性结合。患者的成纤维细胞对高剂量的1,25(OH)(2)D(3)也完全抵抗，这表现为它们未能诱导24 - 羟化酶基因的表达，而该基因是1,25(OH)(2)D(3)活性的标志物。VDR基因的DNA序列分析发现外显子8中有一个独特的C到T突变。该突变将谷氨酰胺密码子改变为氨基酸317处的过早终止密码子（Q317X）。限制性酶切分析表明患者为该突变的纯合子。父母双方均为突变等位基因的杂合子。总之，我们在一名HVDRR患者中鉴定出一种新的VDR突变Q317X，作为分子缺陷。Q317X突变缺失了VDR配体结合域的110个氨基酸，并导致[3H]1,25(OH)(2)D(3)结合和靶基因反式激活丧失。
