Loss-of-Function Mutations of CYP24A1, the Vitamin D 24-Hydroxylase Gene, Cause Long-standing Hypercalciuric Nephrolithiasis and Nephrocalcinosis
Loss-of-Function Mutations of CYP24A1, the Vitamin D 24-Hydroxylase Gene, Cause Long-standing Hypercalciuric Nephrolithiasis and Nephrocalcinosis
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DOI：
10.1016/j.juro.2013.02.3188
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发表时间：
2013-08-01
影响因子：
6.6
通讯作者：
Holtzman, Eli J.
中科院分区：
文献类型：
--
作者：
Dinour, Dganit;Beckerman, Pazit;Holtzman, Eli J.
目的：高钙尿症是肾结石最常见的病因，遗传因素在近一半的肾结石病例中起重要作用。最近，在特发性婴儿高钙血症中发现了编码维生素D24-羟基酶的基因CYP24A1的功能缺失突变。我们描述了由CYP24A1突变引起的成人严重的长期肾结石疾病的临床和分子基础。材料和方法：来自2个以色列家庭的3名患有肾结石和肾钙质沉着症的患者的临床特征。结果：所有受试者均表现为严重的肾结石，经过广泛的评估，其病因数十年来一直未被发现。他们都有高钙尿、肾钙沉着症和间歇性高钙血症，最年长的受试者出现慢性肾功能不全。所有患者都有典型的检测结果，包括正常-高血钙，低甲状旁腺激素水平，高维生素D25-(OH)D-3和1，25-(OH)(2)D-3，低24，25-(OH)(2)D-3。在家系1中发现了3个CYP24A1功能缺失突变，包括家系1中的一个纯合子缺失(DelE143)，以及家系2中的复合杂合突变L409S和新的W268-Stop。结论：编码1，25-二羟基维生素D324-羟基酶的CYP24A1基因功能缺失突变可引起严重的高钙尿性肾结石和肾钙素沉着症。这些突变可能出现在成年人身上，并可能导致慢性肾功能不全。我们的研究结果支持隐性遗传模式。在高钙尿性肾结石的鉴别诊断中应考虑到CYP24A1突变，特别是现在许多成年人服用补充维生素D的处方。
Purpose: Hypercalciuria is the most common cause of kidney stone disease and genetic factors have an important role in nearly half of these cases. Recently loss-of-function mutations of CYP24A1, the gene encoding vitamin D 24-hydroxylase, were identified in idiopathic infantile hypercalcemia. We describe the clinical and molecular basis of severe long-standing kidney stone disease in adults caused by CYP24A1 mutations.Materials and Methods: Three subjects from 2 Israeli families with nephrolithiasis and nephrocalcinosis were clinically characterized. Genomic DNA was isolated from peripheral blood and sequencing of CYP24A1 was performed.Results: All subjects presented with severe kidney stone disease, the cause of which was not discovered for decades despite extensive evaluation. They all had hypercalciuria, nephrocalcinosis and intermittent hypercalcemia, and chronic kidney insufficiency developed in the oldest subject. All patients had a typical pattern of test results, including normal-high serum calcium, low parathyroid hormone levels, high vitamin D 25-(OH)D-3 and 1,25-(OH)(2)D-3, and low 24,25-(OH)(2)D-3. Overall 3 CYP24A1 loss-of-function mutations were identified, including a homozygous deletion (delE143) in consanguinous family 1, and compound heterozygous mutations L409S and the novel W268-stop in family 2.Conclusions: Loss-of-function mutations of CYP24A1 gene, encoding for 1,25-dihydroxyvitamin D3 24-hydroxylase, cause severe hypercalciuric nephrolithiasis and nephrocalcinosis. The mutations may present in adults and may lead to chronic renal insufficiency. Our results support a recessive mode of inheritance. CYP24A1 mutations should be considered in the differential diagnosis of hypercalciuric nephrolithiasis, especially as many adults are now prescribed supplemental oral vitamin D.