{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T21:22:41Z","timestamp":1784323361253,"version":"3.55.0"},"reference-count":64,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,3,29]],"date-time":"2023-03-29T00:00:00Z","timestamp":1680048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DK109398"],"award-info":[{"award-number":["R01DK109398"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DK131049"],"award-info":[{"award-number":["R01DK131049"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["CTSI 106564\/8000063783 PDT"],"award-info":[{"award-number":["CTSI 106564\/8000063783 PDT"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32 GM132024"],"award-info":[{"award-number":["T32 GM132024"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Lowe Syndrome Association, Lowe Syndrome Trust and the Clinical and Translational Science Institute","award":["R01DK109398"],"award-info":[{"award-number":["R01DK109398"]}]},{"name":"Lowe Syndrome Association, Lowe Syndrome Trust and the Clinical and Translational Science Institute","award":["R01DK131049"],"award-info":[{"award-number":["R01DK131049"]}]},{"name":"Lowe Syndrome Association, Lowe Syndrome Trust and the Clinical and Translational Science Institute","award":["CTSI 106564\/8000063783 PDT"],"award-info":[{"award-number":["CTSI 106564\/8000063783 PDT"]}]},{"name":"Lowe Syndrome Association, Lowe Syndrome Trust and the Clinical and Translational Science Institute","award":["T32 GM132024"],"award-info":[{"award-number":["T32 GM132024"]}]},{"name":"NIGMS-funded","award":["R01DK109398"],"award-info":[{"award-number":["R01DK109398"]}]},{"name":"NIGMS-funded","award":["R01DK131049"],"award-info":[{"award-number":["R01DK131049"]}]},{"name":"NIGMS-funded","award":["CTSI 106564\/8000063783 PDT"],"award-info":[{"award-number":["CTSI 106564\/8000063783 PDT"]}]},{"name":"NIGMS-funded","award":["T32 GM132024"],"award-info":[{"award-number":["T32 GM132024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>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\u2019s 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\u2032s 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.<\/jats:p>","DOI":"10.3390\/biom13040615","type":"journal-article","created":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T02:23:46Z","timestamp":1680143026000},"page":"615","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Heterogeneity in Lowe Syndrome: Mutations Affecting the Phosphatase Domain of OCRL1 Differ in Impact on Enzymatic Activity and Severity of Cellular Phenotypes"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4407-0310","authenticated-orcid":false,"given":"Jennifer J.","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8066-2500","authenticated-orcid":false,"given":"Swetha","family":"Ramadesikan","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrianna F.","family":"Black","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Christoffer","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3076-7793","authenticated-orcid":false,"given":"Andres F. Pacheco","family":"Pacheco","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sneha","family":"Subramanian","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia B.","family":"Hanna","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4913-956X","authenticated-orcid":false,"given":"Gillian","family":"Barth","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia V.","family":"Stauffacher","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4091-6614","authenticated-orcid":false,"given":"Daisuke","family":"Kihara","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Department of Computer Science, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruben Claudio","family":"Aguilar","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1111\/tra.12160","article-title":"The cellular and physiological functions of the Lowe syndrome protein OCRL1","volume":"15","author":"Mehta","year":"2014","journal-title":"Traffic"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1007\/s00467-016-3343-3","article-title":"The oculocerebrorenal syndrome of Lowe: An update","volume":"31","author":"Ludwig","year":"2016","journal-title":"Pediatr. 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