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Abstract：
Lowe Syndrome (LS) is a condition due to mutations in the OCRL1 gene, characterized by congenital cataracts, intellectual disability, and kidney malfunction. Unfortunately, patients succumb to renal failure after adolescence. This study is centered in investigating the biochemical and phenotypic impact of patient\'s OCRL1 variants (OCRL1VAR). Specifically, we tested the hypothesis that some OCRL1VAR are stabilized in a non-functional conformation by focusing on missense mutations affecting the phosphatase domain, but not changing residues involved in binding/catalysis. The pathogenic and conformational characteristics of the selected variants were evaluated in silico and our results revealed some OCRL1VAR to be benign, while others are pathogenic. Then we proceeded to monitor the enzymatic activity and function in kidney cells of the different OCRL1VAR. Based on their enzymatic activity and presence/absence of phenotypes, the variants segregated into two categories that also correlated with the severity of the condition they induce. Overall, these two groups mapped to opposite sides of the phosphatase domain. In summary, our findings highlight that not every mutation affecting the catalytic domain impairs OCRL1\'s enzymatic activity. Importantly, data support the inactive-conformation hypothesis. Finally, our results contribute to establishing the molecular and structural basis for the observed heterogeneity in severity/symptomatology displayed by patients.
摘要：
Lowe综合征（LS）是一种由于OCRL1基因突变引起的疾病，以先天性白内障为特征，智力残疾,和肾功能不全.不幸的是,患者在青春期后死于肾功能衰竭。本研究集中于研究患者OCRL1变异体(OCRL1VAR)的生化和表型影响。具体来说,我们检验了这样一个假设，即一些OCRL1VAR通过关注影响磷酸酶结构域的错义突变而稳定在非功能性构象中，但不改变参与结合/催化的残基。所选变体的致病性和构象特征进行了计算机评估，我们的结果表明某些OCRL1VAR是良性的，而其他人是致病的。然后我们继续监测不同OCRL1VAR在肾细胞中的酶活性和功能。基于它们的酶活性和表型的存在/不存在，这些变体分为两个类别，它们也与它们诱导的疾病的严重程度相关。总的来说,这两组映射到磷酸酶结构域的相对侧。总之,我们的研究结果强调，并非所有影响催化结构域的突变都会损害OCRL1的酶活性。重要的是,数据支持非活性构象假说。最后,我们的结果有助于建立观察到的患者严重程度/症状异质性的分子和结构基础.
