Hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia resulting from a novel missense mutation in the DNA-binding domain of the vitamin D receptor.
Hereditary 1,25-dihydroxyvitamin D-resistant rickets with alopecia resulting from a novel missense mutation in the DNA-binding domain of the vitamin D receptor.
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DOI：
10.1016/j.ymgme.2009.09.004
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发表时间：
2010-01
影响因子：
3.8
通讯作者：
Feldman, David
中科院分区：
文献类型：
--
作者：
Malloy, Peter J.;Wang, Jining;Srivastava, Tarak;Feldman, David
罕见的遗传隐性疾病，遗传性维生素D抗性佝偻病（HVDRR），是由维生素D受体（VDR）突变引起的，导致对活性激素1，25-二羟基维生素D3（1，25-（OH）2D 3或骨化三醇）的抗性。在这项研究中，我们检查了一个年轻男孩的VDR与HVDRR的临床特征，包括严重佝偻病，低钙血症，低磷血症和部分脱发。脱发的模式是非常不寻常的总秃发区，邻近正常的头发和头发稀少的地区。口服钙剂和维生素D治疗后，患儿病情没有改善，但静脉钙剂治疗后，他的异常化学物质和骨X光检查正常化。我们发现该儿童是VDR基因中一个独特错义突变的纯合子，该突变将VDR DNA结合结构域（DBD）中第26位氨基酸（V26 M）的缬氨酸转化为甲硫氨酸。在患者培养的皮肤成纤维细胞中研究了突变的VDR，发现其表现出正常的[3 H] 1，25-（OH）2D 3结合和蛋白质表达。然而，成纤维细胞对高浓度1，25（OH）2D 3处理无反应，这通过其未能诱导CYP 24 A1基因表达（1，25（OH）2D 3反应性的标志物）证明。我们在WT VDR中重建了V26 M突变，并表明在转染的COS-7细胞中，该突变消除了1，25（OH）2D 3介导的反式激活。突变VDR表现出正常的配体诱导结合RXRα和共激活因子DRIP 205。然而，V26 M突变抑制VDR与共有维生素D反应元件（VDRE）的结合。总之，我们已经确定了一种新的V26 M突变的VDR DBD的分子缺陷的患者HVDRR和一个不寻常的模式脱发。
The rare genetic recessive disease, hereditary vitamin D resistant rickets (HVDRR), is caused by mutations in the vitamin D receptor (VDR) that result in resistance to the active hormone 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3 or calcitriol). In this study, we examined the VDR from a young boy with clinical features of HVDRR including severe rickets, hypocalcemia, hypophosphatemia and partial alopecia. The pattern of alopecia was very unusual with areas of total baldness, adjacent to normal hair and regions of scant hair. The child failed to improve on oral calcium and vitamin D therapy but his abnormal chemistries and his bone x-rays normalized with intravenous calcium therapy. We found that the child was homozygous for a unique missense mutation in the VDR gene that converted valine to methionine at amino acid 26 (V26M) in the VDR DNA-binding domain (DBD). The mutant VDR was studied in the patient’s cultured skin fibroblasts and found to exhibit normal [3H]1,25-(OH)2D3 binding and protein expression. However, the fibroblasts were unresponsive to treatment with high concentrations of 1,25(OH)2D3 as demonstrated by their failure to induce CYP24A1 gene expression, a marker of 1,25(OH)2D3 responsiveness. We recreated the V26M mutation in the WT VDR and showed that in transfected COS-7 cells the mutation abolished 1,25(OH)2D3-mediated transactivation. The mutant VDR exhibited normal ligand-induced binding to RXRα and to the coactivator DRIP205. However, the V26M mutation inhibited VDR binding to a consensus vitamin D response element (VDRE). In summary, we have identified a novel V26M mutation in the VDR DBD as the molecular defect in a patient with HVDRR and an unusual pattern of alopecia.
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DOI：
10.1016/j.jsbmb.2004.03.058
发表时间：
2004-05-01
影响因子：
4.1
作者：
Goltzman, D;Miao, DS;Hendy, GN
通讯作者：
Hendy, GN
影响因子：
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作者：
Malloy, PJ;Xu, R;Feldman, D
通讯作者：
Feldman, D
影响因子：
5.8
作者：
MALLOY, PJ;HOCHBERG, Z;FELDMAN, D
通讯作者：
FELDMAN, D
影响因子：
4.8
作者：
Panda, DK;Miao, DS;Goltzman, D
通讯作者：
Goltzman, D
DOI：
10.1016/j.jsbmb.2006.11.016
发表时间：
2007-03-01
影响因子：
4.1
作者：
Dixon, K. M.;Deo, S. S.;Mason, R. S.
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Mason, R. S.