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Pediatric Nephrology (Berlin, Germany) Dec 2016The oculocerebrorenal syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, intellectual disability, and... (Review)
Review
The oculocerebrorenal syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, intellectual disability, and proximal renal tubular dysfunction. Whereas the ocular manifestations and severe muscular hypotonia are the typical first diagnostic clues apparent at birth, the manifestations of incomplete renal Fanconi syndrome are often recognized only later in life. Other characteristic features are progressive severe growth retardation and behavioral problems, with tantrums. Many patients develop a debilitating arthropathy. Treatment is symptomatic, and the life span rarely exceeds 40 years. The causative oculocerebrorenal syndrome of Lowe gene (OCRL) encodes the inositol polyphosphate 5-phosphatase OCRL-1. OCRL variants have not only been found in classic Lowe syndrome, but also in patients with a predominantly renal phenotype classified as Dent disease type 2 (Dent-2). Recent data indicate that there is a phenotypic continuum between Dent-2 disease and Lowe syndrome, suggesting that there are individual differences in the ability to compensate for the loss of enzyme function. Extensive research has demonstrated that OCRL-1 is involved in multiple intracellular processes involving endocytic trafficking and actin skeleton dynamics. This explains the multi-organ manifestations of the disease. Still, the mechanisms underlying the wide phenotypic spectrum are poorly understood, and we are far from a causative therapy. In this review, we provide an update on clinical and molecular genetic findings in Lowe syndrome and the cellular and physiological functions of OCRL-1.
Topics: Adolescent; Child; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 11; Humans; Infant; Infant, Newborn; Molecular Biology; Mutation; Oculocerebrorenal Syndrome; WAGR Syndrome
PubMed: 27011217
DOI: 10.1007/s00467-016-3343-3 -
European Journal of Ophthalmology Sep 2020Lowe syndrome is a rare X-linked disease that is characterized by renal dysfunction, developmental delays, congenital cataracts and glaucoma. Mutations in the...
BACKGROUND
Lowe syndrome is a rare X-linked disease that is characterized by renal dysfunction, developmental delays, congenital cataracts and glaucoma. Mutations in the oculocerebral renal syndrome of Lowe () gene are found in Lowe syndrome patients. Although loss of vision is a major concern for families and physicians who take care of Lowe syndrome children, definitive cause of visual loss is still unclear. Children usually present with bilateral dense cataracts at birth and glaucoma, which occurs in more than half of cases, either concurrently or following cataract surgery.
MATERIALS AND METHODS
A retrospective review was conducted on the prevalence and characteristics of ocular findings among families of patients with Lowe syndrome with 137 uniquely affected individuals.
RESULTS
Of 137 patients, all had bilateral congenital cataracts. Nystagmus was reported in 69.3% of cases, glaucoma in 54.7%, strabismus in 35.0%, and corneal scar in 18.2% of patients. Glaucoma was reported as the most common cause of blindness (46%) followed by corneal scars (41%). Glaucoma occurred in 54.7% of patients and affected both eyes in the majority of cases. Of these patients, 55% underwent surgery for glaucoma, while the remaining patients used medications to control their eye pressure. Timolol and latanoprost were the most commonly used medications. Although trabeculectomy and goniotomy are commonly used for pressure management, aqueous tube shunts had the best outcomes.
CONCLUSION
Ocular manifestations in individuals with Lowe syndrome and carriers with mutation are reported which may help familiarize clinicians with the ocular manifestations and management of a rare and complex syndrome.
Topics: Cataract; Cataract Extraction; Child; Child, Preschool; Corneal Diseases; Eye Diseases; Female; Glaucoma; Humans; Infant; Infant, Newborn; Male; Nystagmus, Pathologic; Oculocerebrorenal Syndrome; Phosphoric Monoester Hydrolases; Prevalence; Retrospective Studies; Strabismus
PubMed: 32340490
DOI: 10.1177/1120672120920544 -
Orphanet Journal of Rare Diseases May 2006Lowe syndrome (the oculocerebrorenal syndrome of Lowe, OCRL) is a multisystem disorder characterised by anomalies affecting the eye, the nervous system and the kidney.... (Review)
Review
Lowe syndrome (the oculocerebrorenal syndrome of Lowe, OCRL) is a multisystem disorder characterised by anomalies affecting the eye, the nervous system and the kidney. It is a uncommon, panethnic, X-linked disease, with estimated prevalence in the general population of approximately 1 in 500,000. Bilateral cataract and severe hypotonia are present at birth. In the subsequent weeks or months, a proximal renal tubulopathy (Fanconi-type) becomes evident and the ocular picture may be complicated by glaucoma and cheloids. Psychomotor retardation is evident in childhood, while behavioural problems prevail and renal complications arise in adolescence. The mutation of the gene OCRL1 localized at Xq26.1, coding for the enzyme phosphatidylinositol (4,5) bisphosphate 5 phosphatase, PtdIns (4,5)P2, in the trans-Golgi network is responsible for the disease. Both enzymatic and molecular testing are available for confirmation of the diagnosis and for prenatal detection of the disease. The treatment includes: cataract extraction, glaucoma control, physical and speech therapy, use of drugs to address behavioural problems, and correction of the tubular acidosis and the bone disease with the use of bicarbonate, phosphate, potassium and water. Life span rarely exceeds 40 years.
Topics: Adolescent; Adult; Central Nervous System Diseases; Child; Child, Preschool; Diagnosis, Differential; Eye Diseases; Female; Genetic Carrier Screening; Humans; Infant; Infant, Newborn; Kidney Diseases; Middle Aged; Oculocerebrorenal Syndrome; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Pregnancy; Prenatal Diagnosis; Prognosis; Quality of Life; Young Adult
PubMed: 16722554
DOI: 10.1186/1750-1172-1-16 -
Journal of Medical Genetics Dec 2022Lowe syndrome (LS) is an X linked disease caused by pathogenic variants in the gene that impacts approximately 1 in 500 000 children. Classic features include...
BACKGROUND
Lowe syndrome (LS) is an X linked disease caused by pathogenic variants in the gene that impacts approximately 1 in 500 000 children. Classic features include congenital cataract, cognitive/behavioural impairment and renal tubulopathy.
METHODS
This study is a retrospective review of clinical features reported by family based survey conducted by Lowe Syndrome Association. Frequency of non-ocular clinical feature(s) of LS and their age of onset was summarised. An LS-specific therapy effectiveness scale was used to assess the response to the administered treatment. Expression of and relevant neuropeptides was measured in postmortem human brain by qPCR. Gene expression in the mouse brain was determined by reanalysis of publicly available bulk and single cell RNA sequencing.
RESULTS
A total of 137 individuals (1 female, 89.1% white, median age 14 years (range 0.8-56)) were included in the study. Short stature (height <3rd percentile) was noted in 81% (n=111) individuals, and 15% (n=20) received growth hormone therapy. Undescended testis was reported in 47% (n=64), and median age of onset of puberty was 15 years. Additional features were dental problems (n=77, 56%), bone fractures (n=63, 46%), hypophosphataemia (n=60, 44%), developmental delay and behavioural issues. is expressed in human and mouse hypothalami, and in hypothalamic cell clusters expressing , , , and pituitary cells expressing and .
CONCLUSIONS
There is a wide spectrum of the clinical phenotype of LS. Some of the features may be partly driven by the loss of function of in the hypothalamus and the pituitary.
Topics: Child; Male; Animals; Mice; Female; Humans; Infant; Child, Preschool; Adolescent; Young Adult; Adult; Middle Aged; Oculocerebrorenal Syndrome; Phosphoric Monoester Hydrolases; Phenotype; Cataract; Brain
PubMed: 35803701
DOI: 10.1136/jmedgenet-2022-108490 -
The Journal of Biological Chemistry Jun 2023T-cell acute lymphoblastic leukemia (T-ALL) is one of the deadliest and most aggressive hematological malignancies, but its pathological mechanism in controlling cell...
T-cell acute lymphoblastic leukemia (T-ALL) is one of the deadliest and most aggressive hematological malignancies, but its pathological mechanism in controlling cell survival is not fully understood. Oculocerebrorenal syndrome of Lowe is a rare X-linked recessive disorder characterized by cataracts, intellectual disability, and proteinuria. This disease has been shown to be caused by mutation of oculocerebrorenal syndrome of Lowe 1 (OCRL1; OCRL), encoding a phosphatidylinositol 4,5-bisphosphate [PI(4,5)P] 5-phosphatase involved in regulating membrane trafficking; however, its function in cancer cells is unclear. Here, we uncovered that OCRL1 is overexpressed in T-ALL cells, and knockdown of OCRL1 results in cell death, indicating the essential role of OCRL in controlling T-ALL cell survival. We show OCRL is primarily localized in the Golgi and can translocate to plasma membrane (PM) upon ligand stimulation. We found OCRL interacts with oxysterol-binding protein-related protein 4L, which facilitates OCRL translocation from the Golgi to the PM upon cluster of differentiation 3 stimulation. Thus, OCRL represses the activity of oxysterol-binding protein-related protein 4L to prevent excessive PI(4,5)P hydrolysis by phosphoinositide phospholipase C β3 and uncontrolled Ca release from the endoplasmic reticulum. We propose OCRL1 deletion leads to accumulation of PI(4,5)P in the PM, disrupting the normal Ca oscillation pattern in the cytosol and leading to mitochondrial Ca overloading, ultimately causing T-ALL cell mitochondrial dysfunction and cell death. These results highlight a critical role for OCRL in maintaining moderate PI(4,5)P availability in T-ALL cells. Our findings also raise the possibility of targeting OCRL1 to treat T-ALL disease.
Topics: Humans; Cell Membrane; Cell Survival; Hydrolysis; Oculocerebrorenal Syndrome; Phosphatidylinositol 4,5-Diphosphate; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Phosphoric Monoester Hydrolases; Golgi Apparatus; Ligands; Protein Transport; Calcium Signaling; Mitochondria; Cytosol
PubMed: 37172724
DOI: 10.1016/j.jbc.2023.104812 -
Scientific Reports May 2017Mutations in the OCRL1 gene result in the oculocerebrorenal syndrome of Lowe, with symptoms including congenital bilateral cataracts, glaucoma, renal failure, and...
Mutations in the OCRL1 gene result in the oculocerebrorenal syndrome of Lowe, with symptoms including congenital bilateral cataracts, glaucoma, renal failure, and neurological impairments. OCRL1 encodes an inositol polyphosphate 5-phosphatase which preferentially dephosphorylates phosphatidylinositide 4,5 bisphosphate (PI(4,5)P). We have identified two novel mutations in two unrelated Lowe syndrome patients with congenital glaucoma. Novel deletion mutations are detected at c.739-742delAAAG in Lowe patient 1 and c.1595-1631del in Lowe patient 2. End stage glaucoma in patient 2 resulted in the enucleation of the eye, which on histology demonstrated corneal keloid, fibrous infiltration of the angle, ectropion uvea, retinal gliosis, and retinal ganglion cell loss. We measured OCRL protein levels in patient keratinocytes and found that Lowe 1 patient cells had significantly reduced OCRL protein as compared to the control keratinocytes. Genotype-phenotype correlation of OCRL1 mutations associated with congenital glaucoma revealed clustering of missense and deletion mutations in the 5-phosphatase domain and the RhoGAP-like domain. In conclusion, we report novel OCRL1 mutations in Lowe syndrome patients and the corresponding histopathologic analysis of one patient's ocular pathology.
Topics: Eye; Genotype; Glaucoma; Humans; Keratinocytes; Male; Mutation, Missense; Oculocerebrorenal Syndrome; Pedigree; Phenotype; Phosphoric Monoester Hydrolases; Protein Structure, Tertiary; Sequence Deletion
PubMed: 28473699
DOI: 10.1038/s41598-017-01447-3 -
Journal of Pediatric Genetics Jun 2013The oculocerebrorenal syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, cognitive and behavioral impairment... (Review)
Review
The oculocerebrorenal syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, cognitive and behavioral impairment and a renal proximal tubulopathy in almost all of the patients. Whereas the ocular manifestations and severe hypotonia are present at birth, the renal involvement appears within the first months of life. Patients show progressive growth retardation and may develop a debilitating arthropathy. Treatment is symptomatic and life span rarely exceeds 40 yr. The causative OCRL gene, encodes an inositol polyphosphate 5-phosphatase. OCRL mutations were not only found in classic Lowe syndrome, but also in milder affected patients, classified as having Dent-2 disease. There is a phenotypic continuum within patients with Dent-2 disease and Lowe syndrome, suggesting that there are individual differences in the ability to compensate for loss of enzyme function. Researchers have conducted a large amount of work to understand the etiology responsible for the disease. However, the mechanisms leading to the clinical manifestations are still poorly understood and we are far from an effective therapy. In this review, we have included well-established findings and the most recent progress in understanding Lowe syndrome and Dent-2 disease.
PubMed: 27625841
DOI: 10.3233/PGE-13049 -
Traffic (Copenhagen, Denmark) May 2014Phosphoinositide lipids play a key role in cellular physiology, participating in a wide array of cellular processes. Consequently, mutation of... (Review)
Review
Phosphoinositide lipids play a key role in cellular physiology, participating in a wide array of cellular processes. Consequently, mutation of phosphoinositide-metabolizing enzymes is responsible for a growing number of diseases in humans. Two related disorders, oculocerebrorenal syndrome of Lowe (OCRL) and Dent-2 disease, are caused by mutation of the inositol 5-phosphatase OCRL1. Here, we review recent advances in our understanding of OCRL1 function. OCRL1 appears to regulate many processes within the cell, most of which depend upon coordination of membrane dynamics with remodeling of the actin cytoskeleton. Recently developed animal models have managed to recapitulate features of Lowe syndrome and Dent-2 disease, and revealed new insights into the underlying mechanisms of these disorders. The continued use of both cell-based approaches and animal models will be key to fully unraveling OCRL1 function, how its loss leads to disease and, importantly, the development of therapeutics to treat patients.
Topics: Animals; Genetic Diseases, X-Linked; Humans; Mutation; Nephrolithiasis; Oculocerebrorenal Syndrome; Phosphatidylinositols; Phosphoric Monoester Hydrolases
PubMed: 24499450
DOI: 10.1111/tra.12160