ArticleHuman molecular genetics2020
Lowe syndrome patient cells display mTOR- and RhoGTPase-dependent phenotypes alleviated by rapamycin and statins.
Article in Human molecular genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 13 citations in OpenAlex.
- CRISPR and Gene Augmentation Rescue Trabecular Meshwork Dysfunction in iPSC Models of Lowe Syndrome.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Advances in Diagnosis and Treatment of Inherited Kidney Diseases in Children.Kidney diseases (Basel, Switzerland) · 2024Review
- OCRL1 Deficiency Affects the Intracellular Traffic of ApoER2 and Impairs Reelin-Induced Responses.Biomolecules · 2024Article
- Lymphangioleiomyomatosis and pregnancy: a mini-review.Archives of gynecology and obstetrics · 2024Review
- Heterogeneity in Lowe Syndrome: Mutations Affecting the Phosphatase Domain of OCRL1 Differ in Impact on Enzymatic Activity and Severity of Cellular Phenotypes.Biomolecules · 2023Article
- Recent advances in the understanding of cilia mechanisms and their applications as therapeutic targets.Frontiers in molecular biosciences · 2023Review
- Endocrine and behavioural features of Lowe syndrome and their potential molecular mechanisms.Journal of medical genetics · 2022Article
- Participation of OCRL1, and APPL1, in the expression, proteolysis, phosphorylation and endosomal trafficking of megalin: Implications for Lowe Syndrome.Frontiers in cell and developmental biology · 2022Article
- The Future of Genetic Disease Studies: Assembling an Updated Multidisciplinary Toolbox.Frontiers in cell and developmental biology · 2022Article
- Genotype & phenotype in Lowe Syndrome: specific OCRL1 patient mutations differentially impact cellular phenotypes.Human molecular genetics · 2021Article
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7 authors at 1 institution in 1 country.
Funding
Abstract
Lowe syndrome (LS) is an X-linked developmental disease characterized by cognitive deficiencies, bilateral congenital cataracts and renal dysfunction. Unfortunately, this disease leads to the early death of affected children often due to kidney failure. Although this condition was first described in the early 1950s and the affected gene (OCRL1) was identified in the early 1990s, its pathophysiological mechanism is not fully understood and there is no LS-specific cure available to patients. Here we report two important signaling pathways affected in LS patient cells. While RhoGTPase signaling abnormalities led to adhesion and spreading defects as compared to normal controls, PI3K/mTOR hyperactivation interfered with primary cilia assembly (scenario also observed in other ciliopathies with compromised kidney function). Importantly, we identified two FDA-approved drugs able to ameliorate these phenotypes. Specifically, statins mitigated adhesion and spreading abnormalities while rapamycin facilitated ciliogenesis in LS patient cells. However, no single drug was able to alleviate both phenotypes. Based on these and other observations, we speculate that Ocrl1 has dual, independent functions supporting proper RhoGTPase and PI3K/mTOR signaling. Therefore, this study suggest that Ocrl1-deficiency leads to signaling defects likely to require combinatorial drug treatment to suppress patient phenotypes and symptoms.
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