Novel OCRL1 mutations in patients with the phenotype of dent disease
Novel OCRL1 mutations in patients with the phenotype of dent disease
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DOI：
10.1053/j.ajkd.2006.08.018
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发表时间：
2006-12-01
影响因子：
13.2
通讯作者：
Ludwig, Michael
中科院分区：
文献类型：
--
作者：
Utsch, Boris;Boekenkamp, Arend;Ludwig, Michael
背景资料：Dent病是一种X连锁肾小管病，通常由影响电压门控氯离子通道和氯离子/质子反向转运蛋白CIC-5的突变引起。最近的一项研究表明，OCRL 1（编码磷脂酰肌醇4，5-二磷酸5-磷酸酶（Ocrl））的缺陷通常在Lowe综合征患者中发现突变，也可引起Dent样表型（Dent 2病）。方法：我们调查了来自17个家族的20名CLCN 5阴性男性，他们的表型类似于Dent病的OCRL 1缺陷。结果：在我们的35个具有Dent病表型的家系中，在6个家系中检测到OCRL 1基因突变。所有这些都是新的移码（Q70 RfsX 88和T121 NfsX 122，检测到两次）或错义突变（1257 T和R476 W）。我们的患者没有认知或行为障碍或白内障，这是Lowe综合征的两个典型标志。所有患者的乳酸脱氢酶和/或肌酸激酶水平均轻度升高，这在CLCN 5阳性患者中很少观察到，但在Lowe综合征患者中常见。为了解释OCRL 1突变引起的表型异质性，我们进行了广泛的数据库挖掘和扩展的逆转录酶聚合酶链反应分析，这没有提供任何证据，但未知的（组织特异性）替代OCRL 1转录。结论：OCRL 1基因突变存在于约23%的Dent表型糖尿病患者中。Ocrl的蛋白分选/靶向缺陷可能是这些患者肌酸激酶和乳酸脱氢酶血清浓度轻度升高的原因，也是怀疑与CLCN 5突变无关的Dent病的线索。为什么在Dent 2疾病患者中发现的各种OCRL 1突变不会导致白内障，这一点仍有待阐明。
Background: Dent disease is an X-linked tubulopathy frequently caused by mutations affecting the voltage-gated chloride channel and chloride/proton antiporter CIC-5. A recent study showed that defects in OCRL1, encoding a phosphatidylinositol 4,5-bisphosphate 5-phosphatase (Ocrl) and usually found mutated in patients with Lowe syndrome, also can provoke a Dent-like phenotype (Dent 2 disease). Methods: We investigated 20 CLCN5-negative males from 17 families with a phenotype resembling Dent disease for defects in OCRL1. Results: In our complete series of 35 families with a phenotype of Dent disease, a mutation in the OCRL 1 gene was detected in 6 kindreds. All were novel frameshift (Q70RfsX88 and T121NfsX122, detected twice) or missense mutations (1257T and R476W). None of our patients had cognitive or behavioral impairment or cataracts, 2 classic hallmarks of Lowe syndrome. All patients had mild increases in lactate dehydrogenase and/or creatine kinase levels, which rarely is observed in CLCN5-positive patients, but frequently found in patients with Lowe syndrome. To explain the phenotypic heterogeneity caused by OCRL1 mutations, we performed extensive data-bank mining and extended reverse-transcriptase polymerase chain reaction analysis, which provided no evidence for yet unknown (tissue-specific) alternative OCRL1 transcripts. Conclusion: Mutations in the OCRL1 gene are found in approximately 23% of kindreds with a Dent phenotype. Defective protein sorting/targeting of Ocrl might be the reason for mildly elevated creatine kinase and lactate dehydrogenase serum concentrations in these patients and a clue to suspect Dent disease unrelated to CLCN5 mutations. It remains to be elucidated why the various OCRL1 mutations found in patients with Dent 2 disease do not cause cataracts.