-
Ugeskrift For Laeger Feb 2014Although many congenital diseases present disturbances of the central nervous system, eyes and renal function, only few of these have a defined genetic basis. The first... (Review)
Review
Although many congenital diseases present disturbances of the central nervous system, eyes and renal function, only few of these have a defined genetic basis. The first clinical features of cerebro-oculo-renal diseases usually develop in early childhood and deterioration of kidney function and even end-stage kidney disease may occur in a young age. The syndromes should be considered in patients with retarded growth and development, central nervous system abnormalities, impaired vision or blindness and progressive renal failure.
Topics: Abnormalities, Multiple; Bardet-Biedl Syndrome; Cerebellar Diseases; Cerebellum; Child; Cilia; Ciliary Motility Disorders; Ciliopathies; Encephalocele; Eye Abnormalities; Genetic Predisposition to Disease; Humans; Kidney Diseases, Cystic; Leber Congenital Amaurosis; Oculocerebrorenal Syndrome; Optic Atrophies, Hereditary; Polycystic Kidney Diseases; Retina; Retinitis Pigmentosa
PubMed: 25350305
DOI: No ID Found -
Traffic (Copenhagen, Denmark) Sep 2005Oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder with the hallmark features of congenital cataracts, mental retardation and Fanconi syndrome of the... (Review)
Review
Oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder with the hallmark features of congenital cataracts, mental retardation and Fanconi syndrome of the kidney proximal tubules. OCRL was first described in 1952, and exactly four decades later, the gene responsible was identified and found to encode a protein highly homologous to inositol polyphosphate 5-phosphatase. This suggested that Lowe syndrome may represent an inborn error of inositol phosphate metabolism, and subsequent studies confirmed that such metabolism is indeed perturbed in Lowe syndrome cells. However, the mechanism by which loss of function of the OCRL1 protein brings about Lowe syndrome remains ill defined. In this review, I will discuss our understanding of OCRL1, including where it is localized, what it interacts with and what its possible functions might be. I will then discuss possible mechanisms by which loss of OCRL1 may bring about cellular defects that manifest themselves in the pathology of Lowe syndrome.
Topics: Actins; Alternative Splicing; Endosomes; Golgi Apparatus; Humans; Membrane Proteins; Models, Biological; Mutation; Oculocerebrorenal Syndrome; Phosphoric Monoester Hydrolases; Protein Structure, Tertiary; rac GTP-Binding Proteins
PubMed: 16101675
DOI: 10.1111/j.1600-0854.2005.00311.x -
The FEBS Journal Jan 2020Today, the importance of autophagy in physiological processes and pathological conditions is undeniable. Initially, autophagy merely was described as an evolutionarily... (Review)
Review
Today, the importance of autophagy in physiological processes and pathological conditions is undeniable. Initially, autophagy merely was described as an evolutionarily conserved mechanism to maintain metabolic homeostasis in times of starvation; however, in recent years it is now apparent that autophagy is a powerful regulator of many facets of cellular metabolism, that its deregulation contributes to various human pathologies, including cancer and neurodegeneration, and that its modulation has considerable potential as a therapeutic approach. Different lipid species, including sphingolipids, sterols, and phospholipids, play important roles in the various steps of autophagy. In particular, there is accumulating evidence indicating the minor group of phospholipids called the phosphoinositides as key modulators of autophagy, including the signaling processes underlying autophagy initiation, autophagosome biogenesis and maturation. In this review, we discuss the known functions to date of the phosphoinositides in autophagy and attempt to summarize the kinases and phosphatases that regulate them as well as the proteins that bind to them throughout the autophagy program. We will also provide examples of how the control of phosphoinositides and their metabolizing enzymes is relevant to understanding many human diseases.
Topics: Animals; Autophagy; Humans; Huntington Disease; Myopathies, Structural, Congenital; Neoplasms; Oculocerebrorenal Syndrome; Phosphatidylinositols
PubMed: 31693781
DOI: 10.1111/febs.15127 -
BMC Medical Genomics Sep 2021Oculocerebrorenal syndrome of Lowe is a rare X-linked disorder characterized by congenital cataracts, mental retardation, and proximal tubulopathy. This condition is...
BACKGROUND
Oculocerebrorenal syndrome of Lowe is a rare X-linked disorder characterized by congenital cataracts, mental retardation, and proximal tubulopathy. This condition is caused by a mutation of OCRL gene (located at chromosome Xq26.1), which encodes an inositol polyphosphate 5-phosphatase.
CASE PRESENTATION
We identified two novel OCRL mutations in two unrelated Chinese boys, each with a severe phenotype of Lowe syndrome. A novel de novo deletion (hemizygous c.659_662delAGGG, p.E220Vfs*29) was present in patient 1 and a novel splicing mutation (hemizygous c.2257-2A > T) that was maternally inherited was present in patient 2. A renal biopsy in patient 2 indicated mild mesangial proliferative glomerulonephritis, mild focal mononuclear cells infiltration, and interstitial focal fibrosis. Moreover, renal expression of OCRL-1 protein in patient 2 was significantly reduced compared to a control patient with thin basement membrane disease.
CONCLUSIONS
This study reports two novel OCRL variants associated with severe ocular and neurologic deficiency, despite only mild renal dysfunction. Based on our two patients and a literature review, the genotype-phenotype correlation of OCRL mutations with this severe phenotype of Lowe syndrome suggest a possible clustering of missense, deletion, and nonsense mutations in the 5-phosphatase domain and Rho-GAP domain in the Chinese population.
Topics: Oculocerebrorenal Syndrome
PubMed: 34488756
DOI: 10.1186/s12920-021-01069-9 -
Genetics Research 2022Both Lowe syndrome and Dent-2 disease are caused by variants in the gene. However, the reason why patients with similar gene mutations presented with different...
BACKGROUND
Both Lowe syndrome and Dent-2 disease are caused by variants in the gene. However, the reason why patients with similar gene mutations presented with different phenotypes remains uncertain.
METHODS
Children with hemizygous pathogenic or likely pathogenic variants in were compiled from published and unpublished consecutive cases from China. Furthermore, a Chi-square test was employed to analyze the correlation of the location and types of mutations on the phenotype of children with Lowe syndrome or Dent-2 disease.
RESULTS
Among the total 83 patients, 70.8% (34/48) cases of Lowe syndrome presented with truncating mutations, while only 31.4% (11/35) cases of Dent-2 disease presented with truncating mutation (Χ = 12.662; < 0.001). Meanwhile, the majority of mutations in Dent-2 disease are located in Exon 2-12 (21/35, 60.0%), while the majority of mutations in Lowe syndrome are located in Exon 13-23 (39/48, 81.3%; Χ = 14.922; < 0.001).
CONCLUSIONS
Truncating mutations of the gene were more common in patients with Lowe syndrome than in Dent-2 disease, while mutation is more likely located at exon 2-12 in Dent-2 disease than that in Lowe syndrome. The type and location of mutation are important indicators for the phenotypes in patients with mutation. This is a large cohort study analyzing the genotype-phenotype correlation in patients with Lowe syndrome and Dent-2 disease in China. Our data may improve the interpretation of new variants and genetic counseling. Furthermore, a large international study would be necessary to illustrate the genotype-phenotype correlation in patients with mutations.
Topics: Cohort Studies; Genetic Association Studies; Humans; Mutation; Oculocerebrorenal Syndrome; Phosphoric Monoester Hydrolases
PubMed: 35919034
DOI: 10.1155/2022/1473260 -
Trends in Biochemical Sciences Apr 2012The precise regulation of phosphoinositide lipids in cellular membranes is crucial for cellular survival and function. Inositol 5-phosphatases have been implicated in a... (Review)
Review
The precise regulation of phosphoinositide lipids in cellular membranes is crucial for cellular survival and function. Inositol 5-phosphatases have been implicated in a variety of disorders, including various cancers, obesity, type 2 diabetes, neurodegenerative diseases and rare genetic conditions. Despite the obvious impact on human health, relatively little structural and biochemical information is available for this family. Here, we review recent structural and mechanistic work on the 5-phosphatases with a focus on OCRL, whose loss of function results in oculocerebrorenal syndrome of Lowe and Dent 2 disease. Studies of OCRL emphasize how the actions of 5-phosphatases rely on both intrinsic and extrinsic membrane recognition properties for full catalytic function. Additionally, structural analysis of missense mutations in the catalytic domain of OCRL provides insight into the phenotypic heterogeneity observed in Lowe syndrome and Dent disease.
Topics: Animals; Dent Disease; Humans; Inositol Polyphosphate 5-Phosphatases; Oculocerebrorenal Syndrome; Phosphoric Monoester Hydrolases
PubMed: 22381590
DOI: 10.1016/j.tibs.2012.01.002 -
Journal of Radiology Case Reports Oct 2014Oculocerebrorenal syndrome of Lowe (OCRL) is a multisystem disorder characterized by congenital cataracts, hypotonia, and cognitive developmental delay with renal...
Oculocerebrorenal syndrome of Lowe (OCRL) is a multisystem disorder characterized by congenital cataracts, hypotonia, and cognitive developmental delay with renal complications developing in the first few months of life. Clinical and laboratory findings of Lowe syndrome are well documented. Though a small number of case reports describe the neuroimaging features and the renal ultrasound manifestations of this disease, a comprehensive review of all the imaging manifestations has not been reported. The authors present a case of OCRL and review the neuroimaging and renal ultrasound manifestations of this multisystem disease.
Topics: Brain Diseases; Failure to Thrive; Humans; Infant, Newborn; Kidney Diseases; Magnetic Resonance Imaging; Male; Neuroimaging; Neurologic Examination; Oculocerebrorenal Syndrome; Ultrasonography
PubMed: 25426219
DOI: 10.3941/jrcr.v8i10.1740 -
The New England Journal of Medicine May 1991The oculocerebrorenal syndrome of Lowe is an X-linked disorder whose clinical manifestations include congenital cataracts, mental retardation, and renal tubular...
BACKGROUND
The oculocerebrorenal syndrome of Lowe is an X-linked disorder whose clinical manifestations include congenital cataracts, mental retardation, and renal tubular dysfunction. We investigated growth, renal function, and serum chemistry values in patients with the oculocerebrorenal syndrome to determine the natural history of the disorder and its heterogeneity with respect to these characteristics.
METHODS
Twenty-three patients with the oculocerebrorenal syndrome, ranging in age from 4 months to 31 years, were examined. Height was compared with bone age. Renal function was assessed by measurements of proteinuria, urinary volume, and fractional excretions of potassium, phosphate, carnitine, and amino acids. Creatinine clearance was determined as a measure of glomerular function.
RESULTS
In the oculocerebrorenal syndrome, linear growth decreases after one year of age; bone age lies between chronologic age and height age. Renal dysfunction occurs in the first year of life, characterized by proteinuria (mean [+/- SD], 1.38 +/- 0.77 g of urinary protein per square meter of body-surface area per day; normal, less than or equal to 0.10), generalized aminoaciduria (mean, 686 +/- 505 mumol of urinary amino acid per kilogram of body weight per day; normal, 94 +/- 45), carnitine wasting (mean fractional excretion, 0.10 +/- 0.05; normal, 0.03 +/- 0.01), and phosphaturia progressing into the third decade. Urinary wasting of individual amino acids is milder than in cystinosis, and branched-chain amino acids are relatively spared. Reciprocal serum creatinine levels fall linearly with age, predicting renal failure in the fourth decade. Concentrations of the muscle enzymes creatine kinase, aspartate aminotransferase, and lactate dehydrogenase, as well as of total serum protein, serum alpha 2-globulin, and high-density lipoprotein cholesterol, are elevated.
CONCLUSIONS
Renal glomerular deterioration is slowly progressive in the oculocerebrorenal syndrome. Renal tubular dysfunction begins early and persists; most patients require alkalinization therapy, and many benefit from supplemental potassium, phosphate, calcium, or carnitine. Serum enzyme elevations suggest muscle involvement in the oculocerebrorenal syndrome.
Topics: Adolescent; Adult; Age Determination by Skeleton; Body Height; Body Weight; Child; Child, Preschool; Cholesterol; Glomerular Filtration Rate; Growth; Humans; Infant; Kidney; Oculocerebrorenal Syndrome; Proteinuria; Triglycerides
PubMed: 2017228
DOI: 10.1056/NEJM199105093241904 -
Journal of Applied Research in... Sep 2019There is limited research into the nature and aetiology of temper outbursts in people with intellectual disabilities. In this study, we describe the phenomenology and... (Comparative Study)
Comparative Study
BACKGROUND
There is limited research into the nature and aetiology of temper outbursts in people with intellectual disabilities. In this study, we describe the phenomenology and environmental context of temper outbursts in Lowe syndrome, a rare genetic syndrome in which outbursts are purportedly frequent.
METHOD
A temper outburst interview (TOI) was conducted with caregivers of seventeen individuals with Lowe syndrome to generate an account of the behavioural sequence, common antecedents and consequences of temper outbursts, and to enable comparisons with similar work on Prader-Willi syndrome.
RESULTS
Outbursts in Lowe syndrome were frequently triggered by thwarted goal-directed behaviour and were associated with high levels of physical aggression and property destruction.
CONCLUSIONS
Form and sequence of outbursts showed similarities to Prader-Willi syndrome and to behaviours reported in literature on typically developing children. The results highlight the importance of considering shared aetiology as well as syndrome-specific pathways in the development of outbursts.
Topics: Adolescent; Adult; Aggression; Child; Humans; Male; Oculocerebrorenal Syndrome; Prader-Willi Syndrome; Problem Behavior; Qualitative Research; Young Adult
PubMed: 31144417
DOI: 10.1111/jar.12613 -
Small GTPases Jan 2021Macrophages are important immune sentinels that detect and clear pathogens and initiate inflammatory responses through the activation of surface receptors, including...
Macrophages are important immune sentinels that detect and clear pathogens and initiate inflammatory responses through the activation of surface receptors, including Toll-like receptors (TLRs). Activated TLRs employ complex cellular trafficking and signalling pathways to initiate transcription for inflammatory cytokine programs. We have previously shown that Rab8a is activated by multiple TLRs and regulates downstream Akt/mTOR signalling by recruiting the effector PI3Kγ, but the guanine nucleotide exchange factors (GEF) canonically required for Rab8a activation in TLR pathways is not known. Using GST affinity pull-downs and mass spectrometry analysis, we identified a Rab8 specific GEF, GRAB, as a Rab8a binding partner in LPS-activated macrophages. Co-immunoprecipitation and fluorescence microscopy showed that both GRAB and a structurally similar GEF, Rabin8, undergo LPS-inducible binding to Rab8a and are localised on cell surface ruffles and macropinosomes where they coincide with sites of Rab8a mediated signalling. Rab nucleotide activation assays with CRISPR-Cas9 mediated knock-out (KO) cell lines of GRAB, Rabin8 and double KOs showed that both GEFs contribute to TLR4 induced Rab8a GTP loading, but not membrane recruitment. In addition, measurement of signalling profiles and live cell imaging with the double KOs revealed that either GEF is individually sufficient to mediate PI3Kγ-dependent Akt/mTOR signalling at macropinosomes during TLR4-driven inflammation, suggesting a redundant relationship between these proteins. Thus, both GRAB and Rabin8 are revealed as key positive regulators of Rab8a nucleotide exchange for TLR signalling and inflammatory programs. These GEFs may be useful as potential targets for manipulating inflammation. TLR: Toll-like Receptor; OCRL: oculocerebrorenal syndrome of Lowe protein; PI3Kγ: phosphoinositol-3-kinase gamma; LPS: lipopolysaccharide; GEF: guanine nucleotide exchange factor; GST: glutathione S-transferases; BMMs: bone marrow derived macrophages; PH: pleckstrin homology; GAP: GTPase activating protein; ABCA1: ATP binding cassette subfamily A member 1; GDI: GDP dissociation inhibitor; LRP1: low density lipoprotein receptor-related protein 1.
Topics: Guanine Nucleotide Exchange Factors
PubMed: 30843452
DOI: 10.1080/21541248.2019.1587278