Mutations in CYP24A1 and Idiopathic Infantile Hypercalcemia
Mutations in CYP24A1 and Idiopathic Infantile Hypercalcemia
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DOI：
10.1056/nejmoa1103864
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发表时间：
2011-08-04
影响因子：
158.5
通讯作者：
Konrad, Martin
中科院分区：
文献类型：
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作者：
Schlingmann, Karl P.;Kaufmann, Martin;Konrad, Martin
补充维生素D预防佝偻病是医学上最古老和最有效的预防措施之一，在北美几乎根除了佝偻病。鉴于维生素D的潜在毒性作用，对最佳剂量的建议仍然存在争议，部分原因是20世纪50年代英国在强化乳制品中补充高维生素D期间特发性婴儿高钙血症的发病率增加。我们调查了特发性婴儿高钙血症的分子基础，其特点是严重的高钙血症，未能茁壮成长，呕吐，脱水，和肾calcinosis.METHODSWe使用了一个典型的特发性婴儿高钙血症的家族性病例与怀疑常染色体隐性遗传的候选基因的方法。应用哺乳动物表达系统对已鉴定的维生素D代谢酶CYP 24 A1进行了基因突变检测，CYP 24 A1编码1，25-二羟维生素D-3降解的关键酶25-羟维生素D24-羟化酶。此外，在第二组婴儿中发现了CYP 24 A1突变，这些婴儿在维生素D预防性推注后发生了严重的高钙血症。功能表征显示在所有CYP 24 A1 mutations. CONCLUSIONSSThe的存在CYP 24 A1突变的功能完全丧失解释了增加对维生素D的敏感性在特发性婴儿高钙血症患者，是一个遗传风险因素的发展有症状的高钙血症，可能会引发维生素D预防在其他明显健康的婴儿。
BACKGROUNDVitamin D supplementation for the prevention of rickets is one of the oldest and most effective prophylactic measures in medicine, having virtually eradicated rickets in North America. Given the potentially toxic effects of vitamin D, the recommendations for the optimal dose are still debated, in part owing to the increased incidence of idiopathic infantile hypercalcemia in Britain in the 1950s during a period of high vitamin D supplementation in fortified milk products. We investigated the molecular basis of idiopathic infantile hypercalcemia, which is characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis.METHODSWe used a candidate-gene approach in a cohort of familial cases of typical idiopathic infantile hypercalcemia with suspected autosomal recessive inheritance. Identified mutations in the vitamin D-metabolizing enzyme CYP24A1 were evaluated with the use of a mammalian expression system.RESULTSSequence analysis of CYP24A1, which encodes 25-hydroxyvitamin D 24-hydroxylase, the key enzyme of 1,25-dihydroxyvitamin D-3 degradation, revealed recessive mutations in six affected children. In addition, CYP24A1 mutations were identified in a second cohort of infants in whom severe hypercalcemia had developed after bolus prophylaxis with vitamin D. Functional characterization revealed a complete loss of function in all CYP24A1 mutations.CONCLUSIONSThe presence of CYP24A1 mutations explains the increased sensitivity to vitamin D in patients with idiopathic infantile hypercalcemia and is a genetic risk factor for the development of symptomatic hypercalcemia that may be triggered by vitamin D prophylaxis in otherwise apparently healthy infants.