Renal disease with OCRL1 mutations: Dent-2 or Lowe syndrome?
Renal disease with OCRL1 mutations: Dent-2 or Lowe syndrome?
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OCRL1 突变的肾脏疾病：Dent-2 还是 Lowe 综合征？
DOI：
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发表时间：
2012
影响因子：
0.4
通讯作者：
D. Dinour
中科院分区：
文献类型：
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作者：
N. Levin;D. Dinour
齿状神经病是一种X连锁肾小管病变，以低分子蛋白尿、高钙尿、肾钙素沉着和肾结石为特征，可发展为晚期肾功能衰竭[1，2]。在过去的十年中，位于染色体Xp11.22的CLCN5基因的功能丧失突变一直在Dent病患者中被报道，该基因编码肾氯/质子逆向转运体ClC-5。然而，在大约40%的Dent样表型患者中，没有发现CLCN5突变[4]。2005年，霍佩斯等人提出。[4]首次表明Dent表型也可能是由OCRL1基因突变引起的，OCRL1基因编码位于反式高尔基体网络中的磷脂酰肌醇4，5-磷酸(PIP2)5-磷酸酶。这些发现得到了其他报告的证实[4-6]，并导致了两种类型的Dent病的定义：由CLCN5突变引起的Dent-1(OMIM#300009)和由OCRL1突变引起的Dent-2(OMIM#300555)，约占Dent病例的15%-20%[7]。PIP2 5-磷酸酶由OCRL1基因编码，在人体组织中普遍表达，包括眼、肾和脑，这是Lowe综合征的主要器官。这种蛋白主要分布在高尔基复合体、溶酶体和内体中[8]。ClC-5和PIP25-磷酸酶均表达于近端肾小管上皮细胞的内体，并被认为与多配体受体的循环有关，如megalin和cubilin，这两种受体通常与Dent-1和Dent-2疾病有关。进一步的遗传异质性被认为是存在的，因为有患者表现出Dent病的独特表型，其中没有发现CLCN5或OCRL1基因突变[4]。OCRL1基因也在LOWE的眼脑肾综合征(OMIM#309000)中发生突变，这是一种罕见的X连锁疾病，其特征是双侧先天性白内障、智力低下和非常类似于Dent病患者的肾脏表型的选择性近端小管功能障碍[9]。然而，进行性肾功能衰竭是常见的，通常比Dent-2病更具侵袭性，发生在更早的年龄。因此，Ocrl1功能丧失会导致一系列肾脏症状以及全身症状。在本期《儿科遗传学杂志》上，Bockenhauer等人。[10]报道了他们对来自12个表型类似Dent-2病的14名CLCN5阴性患者的OCRL1缺陷的研究。在其中6名患者中，他们发现了OCRL1基因的三个新突变和另外三个已知突变。这些突变在典型的Lowe综合征患者中都没有被描述过。这些患者的肾脏表型与携带CLCN5基因突变的患者相似，只是肾钙质沉着症的患病率较低。*通讯作者：Dganit Dinour，以色列TEL-Hashmer Chaim Sheba医疗中心肾脏病和高血压科。电子邮件：Dganit.Dinour@sheba.Health.gov.il。儿科遗传学杂志1(2012年)3-5 DOI 10.3233/PGE-2012-002iOS出版社3
Dent disease is an X-linked tubulopathy, characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and nephrolithiasis that may progress to advanced renal failure [1,2]. During the last decade, loss-of-function mutations of the CLCN5 gene, which is located in chromosome Xp11.22 and encodes the renal chloride/proton antiporter ClC-5, have been consistently reported in patients with Dent disease [3]. However, in about 40% of patients with a Dent-like phenotype, no CLCN5 mutations are found [4]. In 2005, Hoopes et al. [4] showed for the first time that the Dent phenotype may also be caused by mutations in the OCRL1 gene, which encodes a phophatidylinositol 4,5-phosphate (PIP2) 5-phosphatase, located in the trans-Golgi network. These findings were confirmed by other reports [4–6] and led to the definition of two types of Dent disease: Dent-1, caused by CLCN5 mutations (OMIM #300009) and Dent-2, caused by OCRL1 mutations (OMIM #300555), which accounts for about 15–20% of Dent cases [7]. PIP2 5-phosphatase, which is encoded by the OCRL1 gene, is expressed ubiquitously in human tissues, including the eyes, kidneys and brain, the main organs involved in Lowe syndrome. This protein is distributed predominantly in the Golgi complex, lysosomes and endosomes [8]. Both ClC-5 and PIP2 5-phosphatase are expressed in endosomes of the proximal tubular cells and thought to be related to the recycling of multi-ligand receptors, such as megalin and cubilin, which are commonly involved in both Dent-1 and Dent-2 disease. Further genetic heterogeneity is assumed to exist, since there are patients expressing the distinctive phenotype of Dent disease, in which no mutation was identified in either CLCN5 or OCRL1 genes [4]. The OCRL1 gene is also mutated in the oculocerebrorenal syndrome of Lowe (OMIM #309000), which is a rare X-linked disorder, characterized by bilateral congenital cataracts, mental retardation and a selective proximal tubular dysfunction very similar to the renal phenotype of patients with Dent disease [9]. However, progressive renal failure is common, and is typically more aggressive and occurs at an earlier age than in Dent-2 disease. Thus, loss of Ocrl1 function can cause a spectrum of renal, as well as systemic symptoms. In this issue of Journal of Pediatric Genetics, Bockenhauer et al. [10] report their study of 14CLCN5 negative patients from 12 families with a phenotype resembling Dent-2 disease, for defects in OCRL1. In six of these patients, they identified three novel mutations and another three known mutations in the OCRL1 gene. None of these mutations has been described in patients with the classic Lowe syndrome. The renal phenotype of these patients was similar to that of patients harboring the CLCN5 gene mutations, except for a lower prevalence of nephrocalcinosis. *Corresponding author: Dganit Dinour, Department of Nephrology and Hypertension, The Chaim Sheba Medical Center, Tel-Hashomer, Israel. E-mail: Dganit.Dinour@sheba.health.gov.il. Journal of Pediatric Genetics 1 (2012) 3–5 DOI 10.3233/PGE-2012-002 IOS Press 3