OCRL1 Mutations in Dent 2 Patients Suggest a Mechanism for Phenotypic Variability
OCRL1 Mutations in Dent 2 Patients Suggest a Mechanism for Phenotypic Variability
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DOI：
10.1159/000213506
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发表时间：
2009-01-01
影响因子：
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通讯作者：
Scheinman, Steven J.
中科院分区：
文献类型：
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作者：
Shrimpton, Antony E.;Hoopes, Richard R., Jr.;Scheinman, Steven J.
背景/目的：齿状神经病是一种与CLCN5(Dent 1)或OCRL1(Dent 2)突变相关的X连锁肾脏近端小管病变。OCRL1突变也会导致LOWE的眼脑肾综合征。方法：对CLCN5基因序列正常的牙髓患者进行OCRL1基因突变测序。通过分析这些突变和所有其他已报道的OCRL1突变，建立了一个将OCRL1突变与所导致的疾病(Dent 2或Lowe‘s)联系起来的模型。结果：6例Dent病男童有新的OCRL1突变：2个错义突变(R301H、G304E)和4个预测产生提前终止密码子的突变(L56DfsX1、S149X、P161PfsX3和M170IfsX1)。其中包括Dent和Friedman报告的一名原始患者。裂隙灯检查发现，只有一名视力正常的男孩患有早期白内障。2例患者无代谢性酸中毒，3例轻度智力低下。对所有已知的OCRL1突变的分析表明，Dent 2突变分为两类，它们与Lowe突变不重叠。生物信息学分析发现，表达的OCRL1剪接变异体有助于解释区分Dent病和Lowe综合征的那些临床特征的变异性。结论：OCRL1突变可以导致Dent病的肾脏表型，而不是酸中毒或典型的Lowe综合征典型的眼部剧烈异常。我们提出了一个模型来解释Dent 2和Lowe‘s之间的表型差异，这是基于OCRL1产生剪接变体的明显不同类别的突变。版权所有(C)2009 S.Karger AG，巴塞尔
Background/Aims: Dent disease is an X-linked renal proximal tubulopathy associated with mutations in CLCN5 (Dent 1) or OCRL1 (Dent 2). OCRL1 mutations also cause the oculocerebrorenal syndrome of Lowe. Methods: Dent patients with normal sequence for CLCN5 were sequenced for mutations in OCRL1. By analyzing these and all other OCRL1 mutations reported, a model relating OCRL1 mutations to the resulting disease (Dent 2 or Lowe's) was developed. Results: Six boys with Dent disease had novel OCRL1 mutations: two missense (R301H, G304E) and four mutations predicted to produce premature termination codons (L56DfsX1, S149X, P161PfsX3, and M170IfsX1). These include one of the original patients reported by Dent and Friedman. Slit lamp examinations revealed early cataracts in only one boy with normal vision. None of these Dent 2 patients had metabolic acidosis; 3 had mild mental retardation. Analysis of all known OCRL1 mutations show that Dent 2 mutations fall into two classes that do not overlap with Lowe mutations. Bioinformatics analyses identified expressed OCRL1 splice variants that help explain the variability of those clinical features that distinguish Dent disease from Lowe syndrome. Conclusions: OCRL1 mutations can cause the renal phenotype of Dent disease, without acidosis or the dramatic eye abnormalities typical of Lowe syndrome. We propose a model to explain the phenotypic variability between Dent 2 and Lowe's based on distinctly different classes of mutations in OCRL1 producing splice variants. Copyright (C) 2009 S. Karger AG, Basel