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)

The oculocerebrorenal syndrome of Lowe (OCRL) is a multisystem disorder characterized by congenital cataracts, mental retardation, and renal Fanconi syndrome. The OCRL1 gene, which, when mutated, is responsible for OCRL, encodes a 105-kD Golgi protein with phosphatidylinositol (4,5)bisphosphate (PtdIn[4,5]P2) 5-phosphatase activity. We have examined the OCRL1 gene in 12 independent patients with OCRL and have found 11 different mutations. Six were nonsense mutations, and one a deletion of one or two nucleotides that leads to frameshift and premature termination. In one, a 1.2-kb genomic deletion of exon 14 was identified. In four others, missense mutations or the deletion of a single codon were found to involve amino acid residues known to be highly conserved among proteins with PtdIns(4,5)P2 5-phosphatase activity. All patients had markedly reduced PtdIns(4,5)P2 5-phosphatase activity in their fibroblasts, whereas the ocrl1 protein was detectable by immunoblotting in some patients with either missense mutations or a codon deletion but was not detectable in those with premature termination mutations. These results confirm and extend our previous observation that the OCRL phenotype results from loss of function of the ocrl1 protein and that mutations are generally heterogeneous. Missense mutations that abolish enzyme activity but not expression of the protein will be useful for studying structure-function relationships in PtdIns(4,5)P2 5-phosphatases.
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PMID:Spectrum of mutations in the OCRL1 gene in the Lowe oculocerebrorenal syndrome. 919 59

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked human genetic disorder characterized by mental retardation, congenital cataracts, and renal tubular dysfunction. The Lowe syndrome gene, OCRL1, encodes a phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi complex. The pathogenesis of Lowe syndrome due to deficiency of a phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi complex is unknown. We have used targeted disruption in embryonic stem cells to make mice deficient in Ocrl1, the mouse homologue for OCRL1, as an animal model for the disease. Surprisingly, mice deficient in Ocrl1 do not develop the congenital cataracts, renal Fanconi syndrome, or neurological abnormalities seen in the human disorder. We hypothesized that Ocrl1 deficiency is complemented in mice by inositol polyphosphate 5-phosphatase (Inpp5b), an autosomal gene that encodes a phosphatidylinositol bisphosphate 5-phosphatase highly homologous to Ocrl1. We created mice deficient in Inpp5b; the mice were viable and fertile without phenotype except for testicular degeneration in males beginning after sexual maturation. We crossed mice deficient in Ocrl1 to mice deficient in Inpp5b. No liveborn mice or embryos lacking both enzymes were found, demonstrating that Ocrl1 and Inpp5b have overlapping functions in mice and suggesting that the lack of phenotype in Ocrl1-deficient mice may be due to compensating Inpp5b function.
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PMID:Functional overlap between murine Inpp5b and Ocrl1 may explain why deficiency of the murine ortholog for OCRL1 does not cause Lowe syndrome in mice. 959 60

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked multisystem disorder with major abnormalities of eyes, nervous system, and kidneys. Clinical manifestations include congenital cataract, mental retardation, and renal tubular dysfunction. A gene (OCRL1) responsible for OCRL was identified by positional cloning and its product OCRL-1 protein was shown to be a phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] 5-phosphatase localized to the Golgi apparatus. We describe three mutations in OCRL1, one in a patient with severe phenotype and two in patients with moderate phenotype (degree of mental retardation and musculoskeletal abnormalities). The patient with severe phenotype had a G-to-A transition at nucleotide (nt) 1,739, causing an Arg-to-Gln substitution at amino acid 577, and one patient with moderate phenotype had a C-to-G transversion at nt 1,812, leading to a His-to-Gln substitution at amino acid 601. Both Arg-577 and His-601 are encoded by exon 15 and are probably important for proper function of this protein, since these are conserved in various enzymes catalyzing dephosphorylation of inositol compounds. In the other patient with the moderate phenotype, there was a G-to-A transition at nt 2,797 located at the 3'-end of exon 22. This substitution led to a skip of the same exon as well as conversion of codon-930 from GCT (Ala) to ACT (Thr) in the normal-size transcript. When we measured the enzyme activity in skin fibroblasts from the three patients, the activity was less than 10%, compared to findings in normal controls. Western blot analysis showed absence or severe decrease in OCRL-1 protein in cell lysates derived from these patients.
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PMID:Oculocerebrorenal syndrome of Lowe: three mutations in the OCRL1 gene derived from three patients with different phenotypes. 963 63

The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked disorder with features of congenital cataracts, Fanconi syndrome of the renal tubule, and mental retardation. The OCRL1 gene has been positionally cloned and shown to encode a phosphatidylinositol 4,5-biphosphate-5-phosphatase. OCRL is thus thought to be an inborn error of inositol polyphosphate metabolism. We analyzed the gene in two Japanese OCRL patients and their families by DNA sequencing and mismatch polymerase chain reaction (PCR) followed by restriction digestion. A novel nonsense mutation (C1399T) replacing the glutamine of codon 391 (Gln 391 Stop) was identified in exon 12 in 1 patient and also in his mother. A novel missense mutation (C1743G) was identified in exon 15 in the second patient. his mother and maternal grandmother. The missense mutation predicts a substitution of serine for arginine (Ser 505 Arg) in a domain highly conserved among the inositol-5-phosphatase family. Our observations expand the range of OCRL1 mutations that cause Lowe syndrome, and will be useful for genetic counseling in these two families.
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PMID:Identification of two novel mutations in the OCRL1 gene in Japanese families with Lowe syndrome. 978 21

PtdIns(4,5)P(2) and PtdIns(4,5)P(2) 5-phosphatases play important roles in diverse aspects of cell metabolism, including protein trafficking. However, the relative importance of the PtdIns(4,5)P(2) 5-phosphatases in regulating PtdIns(4,5)P(2) levels for specific cell processes is not well understood. Ocrl1 is a PtdIns(4,5)P(2) 5-phosphatase that is deficient in the oculocerebrorenal syndrome of Lowe, a disorder characterized by defects in kidney and lens epithelial cells and mental retardation. Ocrl1 was originally localized to the Golgi in fibroblasts, but a subsequent report suggested a lysosomal localization in a kidney epithelial cell line. In this study we defined the localization of ocrl1 in fibroblasts and in two kidney epithelial cell lines by three methods: immunofluorescence, subcellular fractionation, and a dynamic perturbation assay with brefeldin A. We found that ocrl1 was a Golgi-localized protein in all three cell types and further identified it as a protein of the trans-Golgi network (TGN). The TGN is a major sorting site and has the specialized function in epithelial cells of directing proteins to the apical or basolateral domains. The epithelial cell phenotype in Lowe syndrome and the localization of ocrl1 to the TGN imply that this PtdIns(4,5)P(2) 5-phosphatase plays a role in trafficking. (J Histochem Cytochem 48:179-189, 2000)
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PMID:Ocrl1, a PtdIns(4,5)P(2) 5-phosphatase, is localized to the trans-Golgi network of fibroblasts and epithelial cells. 1063 84

Lowe oculocerebrorenal syndrome (OCRL) (MIM 309000) is a rare X-linked multisystem disorder characterized by congenital cataracts, muscular hypotonia, areflexia, mental retardation, maladaptive behavior, renal tubular dysfunction, vitamin-D-resistant rickets, and scoliosis. The underlying gene OCRL1 is located on chromosome Xq25-q26 and contains 24 exons. It encodes a 105-kDa phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P(2)) 5-phosphatase that is localized to the Golgi complex. To confirm the clinical diagnosis and to assess the carrier state of female relatives for genetic counseling we examined 6 independent patients and their families (a total of 23 individuals) using an improved mutation screening strategy for the OCRL1 gene by sequencing of large PCR amplicons. Four novel and two known mutations were identified: three premature terminations caused by either frameshift mutations (1899insT in exon 17 and 2104-2105delGT in exon 18) or a nonsense mutation (1399C > T in exon 12), two missense mutations (1676G > A and 1754C > T in exon 15), and a 6-bp deletion (1609-1614delAAGTAT in exon 14). An ophthalmological examination was performed in all patients and 14 female relatives. All genotypically proven carrier females showed characteristic lenticular opacities, while all proven noncarriers were lacking this phenotypic finding. The results confirm that ophthalmological evaluation is an apparently reliable first-line method to ascertain the carrier state in Lowe oculocerebrorenal syndrome. The high expressivity of lenticular symptoms in OCRL1 gene carriers is consistent with the hypothesis that (PtdIns[4,5]P(2)) 5-phosphatase activity has low functional reserve capacity for maintaining a balanced homeostasis of lenticular metabolism.
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PMID:Carrier assessment in families with lowe oculocerebrorenal syndrome: novel mutations in the OCRL1 gene and correlation of direct DNA diagnosis with ocular examination. 1076 76

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by congenital cataracts, mental retardation, and renal tubular dysfunction. The gene responsible for OCRL was identified by positional cloning and encodes a lipid phosphatase, phosphatidylinositol 4,5, bisphosphate [PtdIns(4,5)P2]5-phosphatase, which localizes to the Golgi apparatus and is suspected to play a role in Golgi vesicular transport [Suchy et al., 1995]. In addition to the ocular and renal manifestations, most boys with OCRL have cognitive problems and maladaptive behaviors including tantrums and stereotypies. We report a boy with a history of congenital cataracts and mild developmental delay who was also found to have hematuria with proteinuria but minimal signs of renal tubular dysfunction. Subsequent renal biopsy was compatible with a diagnosis of a noncomplement fixating chronic glomerulonephritis. Despite the atypical renal findings, skin fibroblast analysis for PtdIns (4,5)P2 5-phosphatase was performed, and enzyme activity was low, consistent with the diagnosis of OCRL. Western blot analysis from cell lysates showed the ocrl protein was decreased in size and amount. Our report shows atypical renal features of OCRL in a mildly affected boy. The possibility of OCRL should be considered in boys with cataracts and glomerular disease, even in the absence of renal tubular defects and frank mental retardation usually associated with the syndrome. Am. J. Med. Genet. 95:461-466, 2000. Published Wiley-Liss, Inc.
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PMID:Unusual renal features of Lowe syndrome in a mildly affected boy. 1114 67

Mutations at the Norrie disease gene locus, NDP, manifest in a broad range of defects. These range from a relatively mild, late-onset, exudative vitreoretinopathy to congenital blindness and sensorineural deafness combined, in some cases, with mental retardation. In addition, extensive deletions involving the NDP locus, located at Xp11.3, the adjacent monoamine oxidadase genes MAOA and MAOB, and additional material, result in a more severe pattern of symptoms. The phenotypes include all or some of the following; mental retardation, involuntary movements, hypertensive crises and hypogonadism. We extended an existing YAC contig to embrace the boundaries of three of the largest deletions and converted this into four PAC contigs. Computer analysis and experimental data have resulted in the identification of several putative loci, including a phosphatase inhibitor 2-like gene (dJ154.1) and a 250-bp sequence which resembles a homeobox domain (dA113.3), 1.2 Mb and 400 kb respectively from the MAO/NDP cluster. The pattern of expression of dJ154.1 suggests that it may represent an important factor contributing to the complex phenotypes of these deletion patients. Hum Mutat 17:523, 2001.
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PMID:Sequence analysis and transcript identification within 1.5 MB of DNA deleted together with the NDP and MAO genes in atypical Norrie disease patients presenting with a profound phenotype. 1138 15

Lowe syndrome is a rare X-linked disorder characterized by bilateral congenital cataracts, renal Fanconi syndrome, and mental retardation. Lowe syndrome results from mutations in the OCRL1 gene, which encodes a phosphatidylinositol 4,5 bisphosphate 5-phosphatase located in the trans-Golgi network. As a first step in identifying the link between ocrl1 deficiency and the clinical disorder, we have identified a reproducible cellular abnormality of the actin cytoskeleton in fibroblasts from patients with Lowe syndrome. The cellular abnormality is characterized by a decrease in long actin stress fibers, enhanced sensitivity to actin depolymerizing agents, and an increase in punctate F-actin staining in a distinctly anomalous distribution in the center of the cell. We also demonstrate an abnormal distribution of two actin-binding proteins, gelsolin and alpha-actinin, proteins regulated by both PIP(2) and Ca(+2) that would be expected to be altered in Lowe cells. Actin polymerization plays a key role in the formation, maintenance, and proper function of tight junctions and adherens junctions, which have been demonstrated to be critical in renal proximal tubule function, and in the differentiation of the lens. These findings point to a general mechanism to explain how this PIP(2) 5-phosphatase deficiency might produce the Lowe syndrome phenotype.
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PMID:The deficiency of PIP2 5-phosphatase in Lowe syndrome affects actin polymerization. 1242 11

The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked disorder characterized by severe mental retardation, congenital cataracts and renal Fanconi syndrome. OCRL1 protein is a phosphatidylinositol 4,5-bisphosphate 5-phosphatase with a C-terminal RhoGAP domain. Considering the pleiotropic cellular functions of Rho GTPases (Rho, Rac and Cdc42) and their dysregulation in several forms of mental retardation, we have investigated the so far unexplored function of the RhoGAP domain of OCRL1. Activated Rac GTPase was found to stably associate with the OCRL1 RhoGAP domain in vitro and to co-immunoprecipitate with endogenous OCRL1. Contrasting with other GAPs, OCRL1 RhoGAP exhibited a significant interaction with GDP bound Rac in vitro. As compared to Rac, other Rho GTPases tested showed reduced (Cdc42) or no binding (RhoA, RhoG) to OCRL1 RhoGAP. Immunofluorescence studies in HEK and COS7 cells and Golgi perturbation assays with Brefeldin A demonstrated that a fraction of endogenous Rac co-localizes with OCRL1 and gamma-adaptin in the trans-Golgi network. The OCRL1 RhoGAP domain showed low Rac GAP activity in vitro, and when expressed in Swiss 3T3 cells induced specific inhibition of RacGTP dependent ruffles, consistent with OCRL1 being an active RacGAP. OCRL1 appears to be a bifunctional protein which, in addition to its PIP2 5-phosphatase activity, binds to Rac GTPase. This novel property may play a role in localizing OCRL1 to the trans-Golgi network. Moreover, loss of OCRL1 RhoGAP and the resulting alteration in Rho pathways may contribute to mental retardation in Lowe syndrome, as illustrated in other forms of X-linked mental retardation.
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PMID:Lowe syndrome protein OCRL1 interacts with Rac GTPase in the trans-Golgi network. 1291 45


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