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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 -
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 -
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 -
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 -
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