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AJNR. American Journal of Neuroradiology 1993Oculocerebrorenal syndrome is an X-linked recessive disorder characterized by congenital ocular abnormalities, mental retardation, renal disease, and metabolic bone...
Oculocerebrorenal syndrome is an X-linked recessive disorder characterized by congenital ocular abnormalities, mental retardation, renal disease, and metabolic bone disease. We report a case of oculocerebrorenal syndrome and, using T1-, proton density-, and T2-weighted imaging sequences, are able to characterize two distinct white matter abnormalities: one lesion is punctate and has signal characteristics that parallel that of cerebrospinal fluid; a second lesion, found in association with the first, consists of patchy white matter abnormalities that are hypointense on T1-weighted images but hyperintense on proton density- and T2-weighted images.
Topics: Brain; Child; Humans; Magnetic Resonance Imaging; Male; Oculocerebrorenal Syndrome
PubMed: 8456727
DOI: No ID Found -
Jornal Brasileiro de Nefrologia 2010Lowe Syndrome, or Oculocerebrorenal Dystrophy (OCRL), has a recessive inheritance linked to X chromosome. It presents cataracts and glaucoma, delay in neuropsychomotor...
INTRODUCTION
Lowe Syndrome, or Oculocerebrorenal Dystrophy (OCRL), has a recessive inheritance linked to X chromosome. It presents cataracts and glaucoma, delay in neuropsychomotor development, cognitive deficits, and renal Fanconi syndrome.
OBJECTIVE
Describe five patients with OCRL, attended at Tubulopathy outpatient clinic.
METHOD
We performed a retrospective assessment of 5 male patient clinical charts of OCRL patients.
RESULTS
Mean age at first consultation was 76.5 and mean follow up interval was 30.5 months (8-53 months). Symptoms and clinical signs included cataracts and nystagmus. Neuropsychomotor development and weight and height deficits were present in whole cases, as well as polyuria, polydipsia, and intestinal constipation, metabolic acidosis, phosphaturia, bicarbonaturia, proteinuria, hypercalciuria, hyperuricosuria. Nephrocalcinosis was identified in one, renal lithiasis in three, and reduced kidney size in two patients. We found pathological fractures and rachitism in two, bone rarefaction and delay of bone age in all of the patients. One patient presented a reduction in the rhythm of glomerular filtration. Therapeutically, all patients received alkali, phosphorus and vitamin D reposition in addition to a dietary orientation adequate to their needs.
CONCLUSION
This study emphasizes the importance of early diagnosis and medico-nutritional followup, to avoid complications related to metabolic disturbances.
Topics: Child; Child, Preschool; Humans; Infant; Male; Oculocerebrorenal Syndrome
PubMed: 21103682
DOI: No ID Found -
International Journal of Molecular... May 2021Lowe syndrome and Dent II disease are X-linked monogenetic diseases characterised by a renal reabsorption defect in the proximal tubules and caused by mutations in the...
Lowe syndrome and Dent II disease are X-linked monogenetic diseases characterised by a renal reabsorption defect in the proximal tubules and caused by mutations in the OCRL gene, which codes for an inositol-5-phosphatase. The life expectancy of patients suffering from Lowe syndrome is largely reduced because of the development of chronic kidney disease and related complications. There is a need for physiological human in vitro models for Lowe syndrome/Dent II disease to study the underpinning disease mechanisms and to identify and characterise potential drugs and drug targets. Here, we describe a proximal tubule organ on chip model combining a 3D tubule architecture with fluid flow shear stress that phenocopies hallmarks of Lowe syndrome/Dent II disease. We demonstrate the high suitability of our in vitro model for drug target validation. Furthermore, using this model, we demonstrate that proximal tubule cells lacking OCRL expression upregulate markers typical for epithelial-mesenchymal transition (EMT), including the transcription factor SNAI2/Slug, and show increased collagen expression and deposition, which potentially contributes to interstitial fibrosis and disease progression as observed in Lowe syndrome and Dent II disease.
Topics: Genetic Diseases, X-Linked; Humans; Kidney Tubules, Proximal; Lab-On-A-Chip Devices; Models, Biological; Mutation; Nephrolithiasis; Oculocerebrorenal Syndrome; Phenotype; Phosphoric Monoester Hydrolases
PubMed: 34069732
DOI: 10.3390/ijms22105361 -
Cellular and Molecular Life Sciences :... Sep 2008Membrane trafficking is crucial in the homeostasis of the highly compartmentalized eukaryotic cells. This compartmentalization occurs both at the organelle level, with... (Review)
Review
Membrane trafficking is crucial in the homeostasis of the highly compartmentalized eukaryotic cells. This compartmentalization occurs both at the organelle level, with distinct organelles maintaining their identities while also intensely interchanging components, and at a sub-organelle level, with adjacent subdomains of the same organelle containing different sets of lipids and proteins. A central question in the field is thus how this compartmentalization is established and maintained despite the intense exchange of components and even physical continuities within the same organelle. The phosphorylated derivatives of phosphatidylinositol, known as the phosphoinositides, have emerged as key components in this context, both as regulators of membrane trafficking and as finely tuned spatial and temporal landmarks for organelle and sub-organelle domains. The central role of the phosphoinositides in cell homeostasis is highlighted by the severe consequences of the derangement of their metabolism caused by genetic deficiencies of the enzymes involved, and from the systematic hijacking of phosphoinositide metabolism that pathogens operate to promote their entry and/or survival in host cells.
Topics: 1-Phosphatidylinositol 4-Kinase; Animals; Autophagy; Cell Membrane; Endocytosis; Homeostasis; Humans; Isoenzymes; Oculocerebrorenal Syndrome; Phosphatidylinositols
PubMed: 18726176
DOI: 10.1007/s00018-008-8353-2 -
Journal of Cell Science Oct 2017Lowe syndrome is a rare X-linked disorder characterized by bilateral congenital cataracts and glaucoma, mental retardation, and proximal renal tubular dysfunction....
Lowe syndrome is a rare X-linked disorder characterized by bilateral congenital cataracts and glaucoma, mental retardation, and proximal renal tubular dysfunction. Mutations in OCRL, an inositol polyphosphate 5-phosphatase that dephosphorylates PI(4,5)P, cause Lowe syndrome. Previously we showed that OCRL localizes to the primary cilium, which has a distinct membrane phospholipid composition, but disruption of phosphoinositides in the ciliary membrane is poorly understood. Here, we demonstrate that cilia from Lowe syndrome patient fibroblasts exhibit increased levels of PI(4,5)P and decreased levels of PI4P. In particular, subcellular distribution of PI(4,5)P build-up was observed at the transition zone. Accumulation of ciliary PI(4,5)P was pronounced in mouse embryonic fibroblasts (MEFs) derived from Lowe syndrome mouse model as well as in -null MEFs, which was reversed by reintroduction of OCRL. Similarly, expression of wild-type OCRL reversed the elevated PI(4,5)P in Lowe patient cells. Accumulation of sonic hedgehog protein in response to hedgehog agonist was decreased in MEFs derived from a Lowe syndrome mouse model. Together, our findings show for the first time an abnormality in ciliary phosphoinositides of both human and mouse cell models of Lowe syndrome.
Topics: Animals; Cell Line; Cilia; Hedgehog Proteins; Humans; Mice; Mice, Knockout; Oculocerebrorenal Syndrome; Phosphatidylinositol 4,5-Diphosphate; Phosphoric Monoester Hydrolases; Receptors, G-Protein-Coupled; Second Messenger Systems; Smoothened Receptor
PubMed: 28871046
DOI: 10.1242/jcs.200857 -
EMBO Reports Jul 2021Lysosomal positioning and mTOR (mammalian target of rapamycin) signaling coordinate cellular responses to nutrient levels. Inadequate nutrient sensing can result in...
Lysosomal positioning and mTOR (mammalian target of rapamycin) signaling coordinate cellular responses to nutrient levels. Inadequate nutrient sensing can result in growth delays, a hallmark of Lowe syndrome. OCRL mutations cause Lowe syndrome, but the role of OCRL in nutrient sensing is unknown. Here, we show that OCRL is localized to the centrosome by its ASH domain and that it recruits microtubule-anchoring factor SSX2IP to the centrosome, which is important in the formation of the microtubule-organizing center. Deficiency of OCRL in human and mouse cells results in loss of microtubule-organizing centers and impaired microtubule-based lysosome movement, which in turn leads to mTORC1 inactivation and abnormal nutrient sensing. Centrosome-targeted PACT-SSX2IP can restore microtubule anchoring and mTOR activity. Importantly, boosting the activity of mTORC1 restores the nutrient sensing ability of Lowe patients' cells. Our findings highlight mTORC1 as a novel therapeutic target for Lowe syndrome.
Topics: Animals; Cell Cycle Proteins; Humans; Lysosomes; Mechanistic Target of Rapamycin Complex 1; Mice; Microtubule-Associated Proteins; Microtubules; Oculocerebrorenal Syndrome; Phosphoric Monoester Hydrolases
PubMed: 33987909
DOI: 10.15252/embr.202052173 -
EMBO Reports Jul 2021Lowe syndrome is a rare, developmental disorder caused by mutations in the phosphatase, OCRL. A study in this issue of EMBO Reports shows that OCRL is required for...
Lowe syndrome is a rare, developmental disorder caused by mutations in the phosphatase, OCRL. A study in this issue of EMBO Reports shows that OCRL is required for microtubule nucleation and that mutations in this protein lead to an inability to activate mTORC1 signaling and consequent cell proliferation in the presence of nutrients. These defects are the result of impaired microtubule-dependent lysosomal trafficking to the cell periphery and are independent of OCRL phosphatase activity.
Topics: Humans; Lysosomes; Mutation; Oculocerebrorenal Syndrome; Phosphoric Monoester Hydrolases; TOR Serine-Threonine Kinases
PubMed: 34047002
DOI: 10.15252/embr.202153232 -
Indian Journal of Anaesthesia Nov 2018Oculocerebrorenal syndrome of Lowe is a rare X-linked metabolic disorder complicated by Fanconi's syndrome. Anaesthetic management of Lowe syndrome with Fanconi's...
Oculocerebrorenal syndrome of Lowe is a rare X-linked metabolic disorder complicated by Fanconi's syndrome. Anaesthetic management of Lowe syndrome with Fanconi's syndrome is challenging to the anaesthesiologists in view of difficult airway due to microcephaly, metabolic abnormalities, and risk of peri-operative seizures. We report a successful anaesthetic management of a case of 2-year-old child scheduled for evaluation under anaesthesia following bilateral lens aspiration surgery.
PubMed: 30532329
DOI: 10.4103/ija.IJA_294_18 -
PloS One 2013Inositol phosphatases are important regulators of cell signaling, polarity, and vesicular trafficking. Mutations in OCRL, an inositol polyphosphate 5-phosphatase, result...
Inositol phosphatases are important regulators of cell signaling, polarity, and vesicular trafficking. Mutations in OCRL, an inositol polyphosphate 5-phosphatase, result in Oculocerebrorenal syndrome of Lowe, an X-linked recessive disorder that presents with congenital cataracts, glaucoma, renal dysfunction and mental retardation. INPP5B is a paralog of OCRL and shares similar structural domains. The roles of OCRL and INPP5B in the development of cataracts and glaucoma are not understood. Using ocular tissues, this study finds low levels of INPP5B present in human trabecular meshwork but high levels in murine trabecular meshwork. In contrast, OCRL is localized in the trabecular meshwork and Schlemm's canal endothelial cells in both human and murine eyes. In cultured human retinal pigmented epithelial cells, INPP5B was observed in the primary cilia. A functional role for INPP5B is revealed by defects in cilia formation in cells with silenced expression of INPP5B. This is further supported by the defective cilia formation in zebrafish Kupffer's vesicles and in cilia-dependent melanosome transport assays in inpp5b morphants. Taken together, this study indicates that OCRL and INPP5B are differentially expressed in the human and murine eyes, and play compensatory roles in cilia development.
Topics: Animals; Cells, Cultured; Cilia; Eye; Humans; Immunohistochemistry; Mice; Microscopy, Fluorescence; Morpholinos; Oculocerebrorenal Syndrome; Phosphoric Monoester Hydrolases; RNA Interference; RNA, Messenger; RNA, Small Interfering; Retinal Pigment Epithelium; Zebrafish
PubMed: 23805271
DOI: 10.1371/journal.pone.0066727 -
Human Molecular Genetics Jun 2020Lowe syndrome (LS) is an X-linked developmental disease characterized by cognitive deficiencies, bilateral congenital cataracts and renal dysfunction. Unfortunately,...
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.
Topics: Cell Line; Cilia; Genetic Diseases, X-Linked; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Oculocerebrorenal Syndrome; Phenotype; Phosphoric Monoester Hydrolases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; rho GTP-Binding Proteins
PubMed: 32391547
DOI: 10.1093/hmg/ddaa086