OCRL-mutated fibroblasts from patients with Dent-2 disease exhibit INPP5B-independent phenotypic variability relatively to Lowe syndrome cells
OCRL-mutated fibroblasts from patients with Dent-2 disease exhibit INPP5B-independent phenotypic variability relatively to Lowe syndrome cells
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DOI：
10.1093/hmg/ddu514
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发表时间：
2015-02-15
影响因子：
3.5
通讯作者：
Dorseuil, Olivier
中科院分区：
文献类型：
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作者：
Montjean, Rodrick;Aoidi, Rifdat;Dorseuil, Olivier
OCRL突变与Lowe综合征和Dent-2病（两种罕见的X连锁疾病）相关。Lowe综合征是一种眼脑肾疾病，而Dent-2患者主要表现为肾近端小管病变。OCRL-1（一种磷酸肌醇-5-磷酸酶）的缺失导致Lowe患者的成纤维细胞中磷脂酰肌醇-4，5-二磷酸（PI（4，5）P2）积累，伴随F-肌动蛋白网络、α-辅肌动蛋白分布和纤毛发生的缺陷，而Dent-2患者的成纤维细胞仍然未被表征。为了寻找与这两种OCRL突变相关病理之间观察到的临床变异性相关的机制，我们比较了来自独立患者的真皮成纤维细胞，其中4例受Dent-2疾病影响，6例患有Lowe综合征。我们首次描述了具有OCRL功能丧失（LOF）突变的Dent-2成纤维细胞表现出肌动蛋白应力纤维减少、点状α-辅肌动蛋白信号出现和初级纤毛形成改变。有趣的是，我们将这些表型定量为Lowe和对照成纤维细胞之间的明显中间值，从而表明这些缺陷的水平与OCRL突变患者之间观察到的临床变异相关。此外，我们发现Lowe和Dent-2成纤维细胞显示出相似的PI（4，5）P2积累水平。最后，我们分析了INPP 5 B，这是一种已经报道与OCRL表现出功能冗余的旁系同源基因，并且没有报告其在RNA或蛋白质水平上的表达差异，也没有报告患者成纤维细胞之间的特定等位基因变异。总之，我们描述了Lowe和Dent-2患者的成纤维细胞之间的差异表型，两者都与OCRL LOF突变相关，我们排除了PI（4，5）P2和INPP 5在这种表型变异中的直接作用，我们强调了导致Lowe综合征中眼部和神经学临床特征的潜在关键改变。
OCRL mutations are associated with both Lowe syndrome and Dent-2 disease, two rare X-linked conditions. Lowe syndrome is an oculo-cerebro-renal disorder, whereas Dent-2 patients mainly present renal proximal tubulopathy. Loss of OCRL-1, a phosphoinositide-5-phosphatase, leads in Lowe patients' fibroblasts to phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) accumulation, with defects in F-actin network, alpha-actinin distribution and ciliogenesis, whereas fibroblasts of Dent-2 patients are still uncharacterized. To search for mechanisms linked to clinical variability observed between these two OCRL mutation-associated pathologies, we compared dermal fibroblasts from independent patients, four affected by Dent-2 disease and six with Lowe syndrome. For the first time, we describe that Dent-2 fibroblasts with OCRL loss-of-function (LOF) mutations exhibit decrease in actin stress fibers, appearance of punctate alpha-actinin signals and alteration in primary cilia formation. Interestingly, we quantified these phenotypes as clearly intermediate between Lowe and control fibroblasts, thus suggesting that levels of these defects correlate with clinical variations observed between patients with OCRL mutations. In addition, we show that Lowe and Dent-2 fibroblasts display similar PI(4,5) P2 accumulation levels. Finally, we analyzed INPP5B, a paralogous gene already reported to exhibit functional redundancy with OCRL, and report neither differences in its expression atRNA or protein levels, nor specific allelic variations between fibroblasts of patients. Altogether, we describe here differential phenotypes between fibroblasts from Lowe and Dent-2 patients, both associated with OCRL LOF mutations, we exclude direct roles of PI(4,5) P2 and INPP5Bin this phenotypic variability and we underline potential key alterations leading to ocular and neurological clinical features in Lowe syndrome.