Disease relevance of OCRL

• The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked human genetic disorder characterized by mental retardation, congenital cataracts, and renal tubular dysfunction [1].
• The oculocerebrorenal syndrome of Lowe (OCRL) is a multisystem disorder characterized by congenital cataracts, mental retardation, and renal Fanconi syndrome [2].
• The oculocerebrorenal syndrome of Lowe (OCRL) is a rare X-linked disorder characterized by severe mental retardation, congenital cataracts and renal Fanconi syndrome [3].
• 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 [4].
• (N Engl J Med 1991; 324: 1318-25), hypercholesterolemia, due to elevated high-density lipoprotein cholesterol (HDL-C) levels, was described as being highly prevalent in OCRL patients [5].

Psychiatry related information on OCRL

• 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 [6].
• 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 [6].

High impact information on OCRL

• Lowe's oculocerebrorenal syndrome (OCRL) is a human X-linked developmental disorder of unknown pathogenesis and has a pleiotropic phenotype affecting the lens, brain and kidneys [7].
• Our results suggest that OCRL may be an inborn error of inositol phosphate metabolism [7].
• Here we use yeast artificial chromosomes with inserts that span the X chromosomal breakpoint from a female OCRL patient in order to isolate complementary DNAs for a gene that is interrupted by the translocation [7].
• Surprisingly, mice deficient in Ocrl1 do not develop the congenital cataracts, renal Fanconi syndrome, or neurological abnormalities seen in the human disorder [1].
• 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 [1].

Chemical compound and disease context of OCRL

• The protein product of the gene that when mutated is responsible for Lowe syndrome, or oculocerebrorenal syndrome (OCRL), is an inositol polyphosphate 5-phosphatase [8].
• Cell lines from kidney proximal tubules of a patient with Lowe syndrome lack OCRL inositol polyphosphate 5-phosphatase and accumulate phosphatidylinositol 4,5-bisphosphate [8].
• 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 [9].

Biological context of OCRL

• The translocation chromosome originated from an unaffected male without a visible translocation, indicating that the most likely cause of OCRL in this patient is the de novo translocation that disrupted the OCRL locus [10].
• The predicted amino acid sequence of the OCRL gene, OCRL-1, was used to develop antibodies against the OCRL-1 protein [11].
• The OCRL medical literature reports the frequency of glaucoma, secondary clinical signs of increased intraocular pressure (IOP), and results of glaucoma surgery, but little information related to the responsible filtration angle abnormalities [12].
• A pair of yeast artificial chromosomes (YACs) that span the Xq25-q26 translocation breakpoint in a female with OCRL were used as probes to screen cDNA libraries made from bovine lens and human kidney [13].
• 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 [2].

Anatomical context of OCRL

• Cell lines from kidney proximal tubules of a patient with Lowe syndrome and a normal individual were used to study the function of OCRL [8].
• OCRL is associated with lysosomal membranes in control proximal tubule cell lines suggesting that OCRL may function in lysosomal membrane trafficking by regulating the specific pool of phosphatidylinositol 4,5-bisphosphate that is associated with lysosomes [8].
• 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 [14].
• By immunofluorescence, the ocrl-1 antibody stains a juxtanuclear region in normal fibroblast cells, while no specific staining is evident in the OCRL patient who produces no transcript [11].
• These domains are present in proteins associated with cilia, flagella, the centrosome and the Golgi complex, and in Hydin and OCRL whose deficiencies are associated with hydrocephalus and Lowe oculocerebrorenal syndrome, respectively [15].

Associations of OCRL with chemical compounds

• These results suggest that OCRL is mainly a lipid phosphatase that may control cellular levels of a critical metabolite, phosphatidylinositol 4,5-bisphosphate [16].
• 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 [17].
• This suggests that Ocrl1 is active as a PIP2 5-phosphatase in Rac induced membrane ruffles [9].
• 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 [18].
• Isolated nephron-segment RT-PCR showed that OCRL-1 is expressed in all segments studied: the glomerulus, proximal tubule, medullary and cortical thick ascending limb, distal convoluted tubule, connecting tubule, cortical collecting duct, and outer medullary collecting duct [19].

Physical interactions of OCRL

• OCRL1 interacts directly with clathrin heavy chain and promotes clathrin assembly in vitro [20].

Other interactions of OCRL

• Analysis of cholesteryl ester transfer protein (CETP) genes, which are now recognized as one of factors increasing serum HDLC levels, revealed the D442G mutation in exon 15 in 5 of 10 family members (1/3 of OCRL patients and 4/7 healthy family members), and no mutation of intron 14 G(+1)-to-A [5].
• We also show that OCRL functions as a phosphatidylinositol 4,5-bisphosphate 5-phosphatase in OCRL-expressing Sf9 cells [16].
• Depletion of cellular OCRL1 also causes partial redistribution of a CI-MPR reporter to early endosomes [20].
• With additional OCRL families made informative for DXS42, theta remained 0 with z = 6.63; and for DXS10 theta = 0.03 and z = 7.07 [21].
• 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 [22].

Analytical, diagnostic and therapeutic context of OCRL

• 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 [23].
• We are using the approaches of linkage analysis, mapping with somatic cell hybrids, and long-range restriction mapping to determine the order of Xq24-q26 markers with respect to each other and to the OCRL locus [24].
• CONCLUSION: A primary X-linked infantile glaucoma is a defining and frequent component of OCRL and is secondary to expression of a primary filtration angle anomaly [12].
• 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 [25].
• Western blot analysis showed absence or severe decrease in OCRL-1 protein in cell lysates derived from these patients [26].

References