Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The oculocerebrorenal syndrome of Lowe (OCRL), an X-linked disorder involving several organ systems, including the eyes, nervous system, and kidneys, is often difficult to diagnose because few pathologic data of diagnostic features about OCRL are available, and its rarity has hampered comprehensive investigations into its clinical spectrum. Recently, the genetic and biochemical abnormalities responsible for this syndrome have been reported. We have synthesized a cDNA probe of the OCRL locus using a polymerase chain reaction, in which there is no homology of cDNA sequence with human inositol polyphosphate-5-phosphatase (HUMINP5P); we have taken a genetic approach to diagnose this disorder in a 10-year-old male by using Northern blotting and have demonstrated the expression of mRNA in human tissues of a 17-week fetus by in situ hybridization. This paper presents a new method that should be an easy and helpful tool for diagnosing OCRL and that contributes a new aspect of this syndrome through in situ hybridization histochemical staining of normal fetal tissues.
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PMID:Clinicopathologic and molecular-pathologic approaches to Lowe's syndrome. 859 26

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by congenital cataracts, cognitive impairment, and renal tubular dysfunction. Although there is a wide range of intellectual function in affected individuals, it is often compromised by a high prevalence of maladaptive behaviors, including tantrums, stubborness, and stereotypy. Whether these behaviors simply reflect the multiple disabilities found in some developmentally impaired individuals with or without OCRL, or a specific genetically-determined behavioral phenotype of OCRL, is unknown. Controls were matched for sex, age, visual impairment, and adaptive functioning and compared with OCRL patients on three standardized measures of adaptive/maladaptive behaviors. Forty-three matched pairs of OCRL and control subjects were identified. Both groups were similar in communication, daily living, socialization, and motor skills, in socioeconomic status, and in measures of parental stress. Individuals with OCRL displayed significantly more severe maladaptive behaviors than control boys, as measured by the Vineland Adaptive Behavior Scales (VABS), with 41% of the difference between the two groups attributable to the diagnosis of OCRL. Twelve maladaptive behaviors measured on the VABS appeared more frequently in OCRL than in controls. Five of these 12 behaviors, i.e., temper tantrums, irritability, complex repetitive behaviors (stereotypy)/mannerisms, obsessions/unusual preoccupations, and negativism, were identified by discriminant function analysis to significantly distinguish between controls and OCRL individuals. The diagnosis of OCRL is associated with a behavioral phenotype consisting of temper tantrums, stereotypy, stubborness, and obsessions/unusual preoccupations. This phenotype cannot be attributed solely to the visual, motor, and intellectual disabilities characteristic of OCRL, and may represent a specific effect of the OCRL gene on the central nervous system.
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PMID:Evidence for a discrete behavioral phenotype in the oculocerebrorenal syndrome of Lowe. 859 50

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by congenital cataracts, renal tubular dysfunction and neurological deficits. The gene responsible for this disorder, OCRL-1, has been cloned and mutations identified in patients. The gene product (ocrl-1) has extensive sequence homology to a 75 kDa inositol polyphosphate 5-phosphatase. We report here that OCRL patients' fibroblasts show no abnormality in inositol polyphosphate 5-phosphatase activity, but are deficient in a phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] 5-phosphatase activity localized to the Golgi apparatus. Direct biochemical diagnosis of this human disease should now be possible. PtdIns(4,5)P2 has been implicated in Golgi vesicular transport through its role in the regulation of ADP-ribosylation factor, phospholipase D and actin assembly in the cytoskeleton. The regulation of PtdIns(4,5)P2 levels by PtdIns(4,5)P2 5-phosphatase may, therefore, be important in the modulation of Golgi vesicular transport. Given that the primary defect in OCRL is a deficiency of a Golgi PtdIns(4,5)P2 phosphatase, we hypothesize that the disorder results from dysregulation of Golgi function and in this way causes developmental defects in the lens and abnormal renal and neurological function.
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PMID:Lowe syndrome, a deficiency of phosphatidylinositol 4,5-bisphosphate 5-phosphatase in the Golgi apparatus. 863 94

The oculocerebrorenal syndrome of Lowe (OCRL; McKusick 309,000) is a rare X-linked disorder characterized by mental retardation, congenital cataracts, and Fanconi syndrome of the proximal renal tubules. We have carried out physical mapping of the OCRL1 gene and determined that it contains 24 exons occupying 58 kb. The gene, located in Xq25-26, is transcribed in a centromeric to telomeric direction. Primers have been developed that allow all coding exons and their intron/exon boundaries to be amplified from genomic DNA for mutation detection. Two tetranucleotide tandem repeat polymorphisms were characterized that immediately flank the OCRL1 gene and, together, are informative in over 90% of females. Variable splicing was seen in the OCRL1 transcript, involving a small 24-bp exon. These results should prove useful to medical and molecular geneticists studying mutations and providing DNA diagnostic services to families dealing with Lowe syndrome as well as to cell biologists interested in structure-function relationships for the OCRL1 protein.
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PMID:Physical mapping and genomic structure of the Lowe syndrome gene OCRL1. 904 11

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

Lowe syndrome (OCRL) is an X-linked disorder involving the eyes, kidney, and nervous system that is caused by loss of function in the OCRL1 gene. OCRL1 contains 24 exons (23 of which are coding) and encodes a 105-kDa enzyme with phosphatidylinositol 4,5 bisphosphate (PtdIns[4,5]P2) 5-phosphatase activity. We published previously (1,2) 13 different mutations in 10 families. Four are missense other 8 mutations in 10 families. Four are missense mutations in highly conserved PtdIns (4,5)P2 5-phosphatase caused by nonsense mutations, and three others are premature terminations caused by frameshift mutations. One frameshift, a GT deletion in exon 21, has been observed previously in two unrelated Lowe syndrome patients, suggesting that it may be a relative "hotspot" for mutation in a disorder marked otherwise by allelic heterogeneity. We have also seen two other recurrent mutations. One is a nonsense mutation CGA > TGA in exon 2 observed in two patients and the second is a missense mutation CGA > CAA in exon 15 present in two unrelated patients. These 21 distinct mutations we have found in 25 Lowe syndrome patients occur in only 9 of the 24 exons: 10, 12, 13, 14, 15, 18, 19, 21, and 22. Interestingly, missense mutations have occurred only in exons 12 through 15 in highly conserved residues among the phosphatidylinositol 5-phosphatases. These observations suggest useful strategies for mutation screening in OCRL.
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PMID:Mutations are not uniformly distributed throughout the OCRL1 gene in Lowe syndrome patients. 968 19

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

The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked disorder with a severe phenotype characterized by congenital cataracts, renal tubular dysfunction and neurological deficits. The gene has been characterized and mutations have been identified in patients. Owing to the allelic heterogeneity exhibited by this gene, prenatal diagnosis by molecular analysis is limited to families in which the mutation is already known or in which linkage is informative. A more generally applicable diagnostic test would be valuable for families at risk for Lowe syndrome. Since ocrl1 is now known to encode a phosphatidylinositol 4,5-bisphosphate 5-phosphatase (Ptdlns(4,5)P2 phosphatase), we assessed whether biochemical testing could be used for prenatal diagnosis. We report here the first case of prenatal diagnosis for Lowe syndrome by measuring phosphatidylinositol 4,5-bisphosphate 5-phosphatase activity in cultured amniocytes.
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PMID:First report of prenatal biochemical diagnosis of Lowe syndrome. 985 17

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by major abnormalities of eyes, nervous system, and kidneys. Mutations in the OCRL1 gene have been associated with the disease. OCRL1 encodes a phosphatidylinositol 4, 5-biphosphate (PtdIns[4,5]P2) 5-phosphatase. We have examined the OCRL1 gene in eight unrelated patients with OCRL and have found seven new mutations and one recurrent in-frame deletion. Among the new mutations, two nonsense mutations (R317X and E558X) and three other frameshift mutations caused premature termination of the protein. A missense mutation, R483G, was located in the highly conserved PtdIns(4,5)P2 5-phosphatase domain. Finally, one frameshift mutation, 2799delC, modifies the C-terminal part of OCRL1, with an extension of six amino acids. Altogether, 70% of missense mutations are located in exon 15, and 52% of all mutations cluster in exons 11-15. We also identified two new microsatellite markers for the OCRL1 locus, and we detected a germline mosaicism in one family. This observation has direct implications for genetic counseling of Lowe syndrome families.
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PMID:Characterization of a germline mosaicism in families with Lowe syndrome, and identification of seven novel mutations in the OCRL1 gene. 1036 18


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