Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) caused by a VDR mutation: A novel mechanism of dominant inheritance.
Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) caused by a VDR mutation: A novel mechanism of dominant inheritance.
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DOI：
10.1016/j.bonr.2015.05.001
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发表时间：
2015-06
期刊：
影响因子：
2.5
通讯作者：
Kitanaka S
中科院分区：
文献类型：
--
作者：
Isojima T;Ishizawa M;Yoshimura K;Tamura M;Hirose S;Makishima M;Kitanaka S
遗传性抗1，25-二羟维生素D佝偻病（HVDRR）是由VDR基因突变引起的，其遗传为常染色体隐性遗传。在这份报告中，我们的目的是确认HVDRR是否偶尔作为显性性状遗传。一名18个月大的日本男孩被评估为身材矮小和罗圈腿。他的父亲在童年时曾因佝偻病接受治疗，他的祖父有罗圈腿。我们根据实验室数据和佝偻病的放射学证据诊断他患有HVDRR。对VDR进行了序列分析，并分析了检测到的突变的功能后果的转录活性、配体结合以及与维甲酸X受体、辅因子和维生素D反应元件（VDRE）的相互作用。在该患者中发现了一种新的突变（Q400 LfsX 7）和一种已报告的变异（R370 H）。其父亲为杂合子Q400 LfsX 7，母亲为杂合子R370 H。功能研究表明，Q400 LfsX 7-VDR的转录活性明显受到干扰。该突变体对野生型VDR具有显性负效应，Q400 LfsX 7-VDR的配体结合亲和力完全受损。有趣的是，Q400 LfsX 7-VDR与辅阻遏物NCoR有很强的相互作用，并且可以在没有配体的情况下与VDRE相互作用。R370 H-VDR在功能上与野生型VDR相似。总之，我们发现了一种显性负性VDR突变体通过组成性辅阻遏物相互作用引起显性遗传HVDRR，这种机制类似于显性遗传甲状腺激素受体突变。我们的报告和一个家系报告一起提示HVDRR的独特遗传，丰富了我们对VDR异常的理解。我们报告了一个显性遗传性维生素D抵抗性佝偻病的家系。在该家系中发现了一种新的VDR突变（Q400 LfsX 7）。该突变体对野生型VDR具有显性负效应，并与辅阻遏物NCoR强烈相互作用。显性遗传的机制与显性遗传的甲状腺激素受体突变相似。
Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is caused by mutations in the VDR gene, and its inheritance is autosomal recessive. In this report, we aimed to confirm whether HVDRR is occasionally inherited as a dominant trait. An 18-month-old Japanese boy was evaluated for short stature and bowlegs. His father had been treated for rickets during childhood, and his paternal grandfather had bowlegs. We diagnosed him with HVDRR based on laboratory data and radiographic evidence of rickets. Sequence analyses of VDR were performed, and the functional consequences of the detected mutations were analyzed for transcriptional activity, ligand binding, and interaction with the retinoid X receptor, cofactors, and the vitamin D response element (VDRE). A novel mutation (Q400LfsX7) and a reported variant (R370H) were identified in the patient. Heterozygous Q400LfsX7 was detected in his father, and heterozygous R370H was detected in his healthy mother. Functional studies revealed that the transcriptional activity of Q400LfsX7-VDR was markedly disturbed. The mutant had a dominant-negative effect on wild-type-VDR, and the ligand binding affinity of Q400LfsX7-VDR was completely impaired. Interestingly, Q400LfsX7-VDR had a strong interaction with corepressor NCoR and could interact with VDRE without the ligand. R370H-VDR was functionally similar to wild-type-VDR. In conclusion, we found a dominant-negative mutant of VDR causing dominantly inherited HVDRR through a constitutive corepressor interaction, a mechanism similar to that in dominantly inherited thyroid hormone receptor mutations. Our report together with a reported pedigree suggested a distinct inheritance of HVDRR and enriched our understanding of VDR abnormalities. We report the pedigree of dominantly inherited hereditary vitamin D resistant rickets. A novel VDR mutation (Q400LfsX7) was identified in the pedigree. The mutant had a dominant-negative effect on the wild type VDR and interacted strongly with corepressor NCoR. The mechanism for dominantly inheritance was similar to that in dominantly inherited thyroid hormone receptor mutations.