Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oculocerebrorenal Lowe syndrome is a rare X-linked disorder characterized by bilateral cataract, mental retardation and renal Fanconi syndrome. The Lowe syndrome protein Ocrl1 is a PIP2 5-phosphatase, primarily localized to the trans-Golgi network (TGN), which 'loss of function' mutations result in PIP2 accumulation in patient's cells. Although PIP2 is involved in many cell functions including signalling, vesicle trafficking and actin polymerization, it has been difficult so far to decipher molecular/cellular mechanisms responsible for Lowe syndrome phenotype. We have recently shown that, through its C-terminal RhoGAP domain, Ocrl1 forms a stable complex with Rac GTPase within the cell. In line with this finding, we report here that upon epidermal growth factor induced Rac activation in COS-7 cells, a fraction of Ocrl1 translocates from TGN to plasma membrane and concentrates in membrane ruffles. In order to investigate the functionality of Ocrl1 in plasma membrane, we have analysed PIP2 distribution in human dermal fibroblasts (HDFs) from Lowe patients versus control HDFs. As revealed by both immunodetection and green fluorescent protein-PH binding, PIP2 was found strikingly to accumulate in PDGF induced ruffles in Lowe HDFs when compared with control. This suggests that Ocrl1 is active as a PIP2 5-phosphatase in Rac induced membrane ruffles. Cellular properties such as cell migration and establishment of cell-cell contacts, which depend on ruffling and lamellipodia formation, should be further investigated to understand the pathophysiology of Lowe syndrome.
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PMID:Lowe syndrome protein Ocrl1 is translocated to membrane ruffles upon Rac GTPase activation: a new perspective on Lowe syndrome pathophysiology. 1582 1

The oculo-cerebro-renal syndrome of Lowe (OCRL) is a rare X-chromosomal disorder characterised by the triad of congenital cataracts, renal tubular dysfunction, and mental retardation. Typically complete opacification and discoid deformation of the lenses are seen, indicating a developmental defect in early embryogenesis. We report on a 35-year-old patient with a mild Lowe syndrome phenotype including incomplete lenticular opacities. Clinical findings suggest that the gene product of the mutated allele (IVS19 + 1G > A) identified in the patient exhibits some residual function.
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PMID:[Clinical findings in a patient with Lowe syndrome and a splice site mutation in the OCRL1 gene]. 1738 24

The Lowe syndrome (LS) is a life-threatening, developmental disease characterized by mental retardation, cataracts and renal failure. Although this human illness has been linked to defective function of the phosphatidylinositol 5-phosphatase, Ocrl1 (Oculo-Cerebro-Renal syndrome of Lowe protein 1), the mechanism by which this enzyme deficiency triggers the disease is not clear. Ocrl1 is known to localize mainly to the Golgi apparatus and endosomes, however it translocates to plasma membrane ruffles upon cell stimulation with growth factors. The functional implications of this inducible translocation to the plasma membrane are presently unknown. Here we show that Ocrl1 is required for proper cell migration, spreading and fluid-phase uptake in both established cell lines and human dermal fibroblasts. We found that primary fibroblasts from two patients diagnosed with LS displayed defects in these cellular processes. Importantly, these abnormalities were suppressed by expressing wild-type Ocrl1 but not by a phosphatase-deficient mutant. Interestingly, the homologous human PI-5-phosphatase, Inpp5b, was unable to complement the Ocrl1-dependent cell migration defect. Further, Ocrl1 variants that cannot bind the endocytic adaptor AP2 or clathrin, like Inpp5b, were less apt to rescue the migration phenotype. However, no defect in membrane recruitment of AP2/clathrin or in transferrin endocytosis by patient cells was detected. Collectively, our results suggest that Ocrl1, but not Inpp5b, is involved in ruffle-mediated membrane remodeling. Our results provide new elements for understanding how Ocrl1 deficiency leads to the abnormalities associated with the LS.
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PMID:Lowe syndrome patient fibroblasts display Ocrl1-specific cell migration defects that cannot be rescued by the homologous Inpp5b phosphatase. 1970 Apr 99

Lowe's syndrome is a rare inherited metabolic disorder characterized by mental retardation, kidney malfunction, and abnormalities of the eyes and bones. A 4 month-old child with Lowe's and Fanconi's syndrome, undergoing bilateral congenital cataract surgery, is presented. Preoperative electrolyte imbalance was corrected by potassium, calcium, magnesium, phosphate, and bicarbonate supplementation. Anesthesia was administered uneventfully using appropriate anesthetic agents and monitoring. Adequate preoperative evaluation and optimization, along with selection of anesthetic agents and fluid and electrolyte management with appropriate perioperative monitoring, is key to a successful outcome.
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PMID:Lowe's syndrome with Fanconi syndrome for ocular surgery: perioperative anesthetic considerations. 2110 39

Oculocerebral renal syndrome of Lowe (OCRL or Lowe syndrome), a severe X-linked congenital disorder characterized by congenital cataracts and glaucoma, mental retardation and kidney dysfunction, is caused by mutations in the OCRL gene. OCRL is a phosphoinositide 5-phosphatase that interacts with small GTPases and is involved in intracellular trafficking. Despite extensive studies, it is unclear how OCRL mutations result in a myriad of phenotypes found in Lowe syndrome. Our results show that OCRL localizes to the primary cilium of retinal pigment epithelial cells, fibroblasts and kidney tubular cells. Lowe syndrome-associated mutations in OCRL result in shortened cilia and this phenotype can be rescued by the introduction of wild-type OCRL; in vivo, knockdown of ocrl in zebrafish embryos results in defective cilia formation in Kupffer vesicles and cilia-dependent phenotypes. Cumulatively, our data provide evidence for a role of OCRL in cilia maintenance and suggest the involvement of ciliary dysfunction in the manifestation of Lowe syndrome.
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PMID:OCRL localizes to the primary cilium: a new role for cilia in Lowe syndrome. 2254 76

Ten percent of cases of intellectual deficiency in boys are caused by genes located on the X chromosome. X-linked mental retardation (XLMR) includes more than 200 syndromes and 80 genes identified to date. The fragile X syndrome is the most frequent syndrome, due to a dynamic mutation with a CGG triplet amplification. Mental retardation is virtually always present. Phonological and syntactic impairments are often combined with pragmatic language impairment and visuospatial reasoning difficulties. A minority fulfill the criteria for autism. In girls, the clinical expression of the complete mutation varies according to the X chromosome inactivation profile. Several XLMR occur as severe early onset encephalopathies: Lowe oculocerebrorenal syndrome, ATR-X syndrome (alpha thalassemia/mental retardation X-linked), Allan-Herdon-Dudley syndrome (MCT8 gene). Two genes, ARX (X-LAG; Partington syndrome) and MECP2 (Rett syndrome in females; mild MR with spastic diplegia/psychotic problems in males) are associated with various phenotypes, according to the mutation involved. Oligophrenine 1 (OPHN-1) gene mutations lead to vermal dysplasia. PQBP1 gene mutations (Renpenning syndrome) are responsible for moderate to severe mental deficiency, microcephaly, and small stature. Although some forms of XLMR are not very specific and the phenotype for each given gene is somewhat heterogeneous, a clinical diagnostic strategy is emerging.
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PMID:X-linked mental deficiency. 2362 80

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)P2, 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)P2 and decreased levels of PI4P. In particular, subcellular distribution of PI(4,5)P2 build-up was observed at the transition zone. Accumulation of ciliary PI(4,5)P2 was pronounced in mouse embryonic fibroblasts (MEFs) derived from Lowe syndrome mouse model as well as in Ocrl-null MEFs, which was reversed by reintroduction of OCRL. Similarly, expression of wild-type OCRL reversed the elevated PI(4,5)P2 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.
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PMID:Loss of OCRL increases ciliary PI(4,5)P2 in Lowe oculocerebrorenal syndrome. 2887 Oct 46

Lowe syndrome (the oculo-cerebro-renal syndrome of Lowe, OCRL) is a multi-system disorder that affects the eyes, nervous system, and kidney. OCRL is a rare X-linked recessive disease with a prevalence of approximately 1 : 500,000. The clinical features of OCRL include congenital cataracts, growth and mental retardation, areflexia, hypotonia, and renal tubular dysfunction (Fanconi-type). Chronic metabolic acidosis and hypotonia may be the most important component affecting management of the peri-anesthetic period during general anesthesia. However, problems such as electrolyte imbalance, seizure, fragility of the bone structures, and increased intraocular pressure should also be considered during the perioperative period. We report here the perioperative management of a patient with Lowe syndrome during the removal of multiple scalp cysts under general anesthesia.
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PMID:The perioperative management of a patient with lowe syndrome for general anesthesia: A case report. 3062 6


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