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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 -
Genomics Sep 1990The Lowe oculocerebrorenal syndrome (OCRL) is characterized by congenital cataract, mental retardation, and renal tubular dysfunction. We are using the approaches of...
The Lowe oculocerebrorenal syndrome (OCRL) is characterized by congenital cataract, mental retardation, and renal tubular dysfunction. 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. DXS42 and DXS100 are proximal to the translocation breakpoint in a female patient with OCRL and a de novo translocation t(X;3)(q25;q27). DXS10, DXS86, HPRT, and DXS177 are distal to the breakpoint. These flanking markers show tight linkage to the disease locus in 11 families segregating for OCRL. Results from field inversion gel analysis show that DXS86 and DXS10 share a 460-kb BssHII fragment. Multipoint analysis to determine the position of HPRT with respect to (DXS10,DXS86) suggests that HPRT is proximal to (DXS10,DXS86). We propose the following order for markers in Xq24-q26: Xcen-(DXS42,DXS37,DXS100)-OCRL-DXS53 -HPRT-[(DXS10,DXS86),DXS177]-Xqter. The identification of additional tightly linked flanking markers extends the number of markers available for use in genetic counseling and begins to define the physical map of the region containing the gene for OCRL.
Topics: Blotting, Southern; Chromosome Mapping; DNA; Data Interpretation, Statistical; Electrophoresis, Agar Gel; Female; Genetic Linkage; Genetic Markers; Humans; Hybrid Cells; Male; Oculocerebrorenal Syndrome; Translocation, Genetic; X Chromosome
PubMed: 2081601
DOI: 10.1016/0888-7543(90)90226-k -
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 -
Endocrinology, Diabetes & Metabolism... 2017This case, presenting with bilateral impalpable testes, illustrates the relevance of a broad differential disorders of sex development case management. It provides new...
SUMMARY
This case, presenting with bilateral impalpable testes, illustrates the relevance of a broad differential disorders of sex development case management. It provides new insights on hypothalamic-pituitary-gonadal (HPG) axis and testicular function abnormalities in the multisystem disorder of Lowe syndrome. Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare disorder characterised by eye abnormalities, central nervous system involvement and proximal renal tubular acidosis. There are a handful of reports of pubertal delay, infertility and cryptorchidism in Lowe syndrome. Biochemistry aged 72 h: testosterone 6.4 nmol/L, LH <0.5 IU/L and FSH <0.5 IU/L. Gonadotropin-releasing hormone stimulation test identified significantly raised baseline LH = 45.4 IU/L (contrasts with earlier undetectable LH), with a 20% increase on stimulation, while baseline FSH = 4.3 IU/L with no increase on stimulation. Day 14 HCG stimulation test produced an acceptable 50% increase in testosterone. The constellation of further abnormalities suggested Lowe syndrome: hypotonia, bilateral cataracts (surgical extraction and intraocular lens implantation) and renal tubular acidosis (microscopic haematuria, hypercalciuria, proteinuria, generalised aminoaciduria, hypophosphataemia and metabolic acidosis). DNA sequencing identified hemizygous frameshift mutation OCRL c.2409_2410delCT in exon 22. Interpretation of initial and repeat GnRH and HCG testing indicates the likelihood of testicular failure. Partial testicular descent occurred but left orchidopexy was required. Improving long-term gonadal function in Lowe syndrome assumes increased importance for current cohorts as advances in renal replacement therapy have greatly improved life expectancy. Noting HPG axis abnormalities in Lowe syndrome in infancy can identify cases requiring increased surveillance of pubertal progress for earlier detection and management.
LEARNING POINTS
Clinical endocrine problems in Lowe syndrome has been reported, but has focused on abnormalities in adolescence and young adulthood: pubertal delay and infertility.We present an infant with isolated LH elevation at baseline and on GnRH stimulation testing who also had bilateral impalpable testes.Early testing of the HPG axis in patients with Lowe syndrome may help predict gonadal abnormalities from a younger age, which will enhance the overall case management into adolescence.
PubMed: 28469921
DOI: 10.1530/EDM-17-0042 -
Journal of Lipid Research Feb 2019Phosphoinositides (PIs) are recognized as major signaling molecules in many different functions of eukaryotic cells. PIs can be dephosphorylated by multiple phosphatase... (Review)
Review
Phosphoinositides (PIs) are recognized as major signaling molecules in many different functions of eukaryotic cells. PIs can be dephosphorylated by multiple phosphatase activities at the 5-, 4-, and 3- positions. Human PI 5-phosphatases belong to a family of 10 members. Except for inositol polyphosphate 5-phosphatase A, they all catalyze the dephosphorylation of PI(4,5)P and/or PI(3,4,5)P at the 5- position. PI 5-phosphatases thus directly control the levels of PI(3,4,5)P and participate in the fine-tuning regulatory mechanisms of PI(3,4)P and PI(4,5)P Second messenger functions have been demonstrated for PI(3,4)P in invadopodium maturation and lamellipodia formation. PI 5-phosphatases can use several substrates on isolated enzymes, and it has been challenging to establish their real substrate in vivo. PI(4,5)P has multiple functions in signaling, including interacting with scaffold proteins, ion channels, and cytoskeleton proteins. PI 5-phosphatase isoenzymes have been individually implicated in human diseases, such as the oculocerebrorenal syndrome of Lowe, through mechanisms that include lipid control. Oncogenic and tumor-suppressive functions of PI 5-phosphatases have also been reported in different cell contexts. The mechanisms responsible for genetic diseases and for oncogenic or tumor-suppressive functions are not fully understood. The regulation of PI 5-phosphatases is thus crucial in understanding cell functions.
Topics: Animals; Cells; Disease; Humans; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Signal Transduction
PubMed: 30194087
DOI: 10.1194/jlr.R087908 -
Korean Journal of Pediatrics Mar 2014Lowe syndrome is a rare, X-linked recessive disorder caused by mutations in the OCRL gene. It involves multiple anatomic systems, particularly the eyes, central nervous...
PURPOSE
Lowe syndrome is a rare, X-linked recessive disorder caused by mutations in the OCRL gene. It involves multiple anatomic systems, particularly the eyes, central nervous system, and kidneys, and leads to profound growth failure and global developmental delay. This study evaluated the clinical and genetic characteristics of Korean patients with Lowe syndrome.
METHODS
The clinical findings and results of genetic studies were reviewed for 12 male patients diagnosed with Lowe syndrome at a single medical institution.
RESULTS
The mean age of the patients at presentation was 2.2 months (range, 0-4 months), although the diagnosis was delayed by a mean of 2.8 years (range, 0-9.7 years). The mean follow-up period was 9.0 years (range, 0.6-16.7 years). Nine mutations in OCRL were identified in 11 patients (92%), with three novel mutations. The main presentation was congenital cataract in both eyes necessitating early cataract removal in the 11 patients with impaired visual acuity. Profound short stature and developmental delay were observed in all patients, and seizures occurred in 50% of the patients. All patients suffered from proximal renal tubular dysfunction, and one patient developed chronic renal failure. Other manifestations included pathologic fracture (50%), cutaneous cysts (42%), and cryptorchidism (42%). However, there was no bleeding tendency, and none of the patients died during the study period.
CONCLUSION
This study describes the clinical and genetic characteristics of Korean patients with Lowe syndrome. The observations are helpful for understanding the natural courses of Lowe syndrome and for appropriate genetic counseling.
PubMed: 24778696
DOI: 10.3345/kjp.2014.57.3.140 -
Current Biology : CB Mar 2019During cytokinesis, an actomyosin contractile ring drives the separation of the two daughter cells. A key molecule in this process is the inositol lipid PtdIns(4,5)P,...
During cytokinesis, an actomyosin contractile ring drives the separation of the two daughter cells. A key molecule in this process is the inositol lipid PtdIns(4,5)P, which recruits numerous factors to the equatorial region for contractile ring assembly. Despite the importance of PtdIns(4,5)P in cytokinesis, the regulation of this lipid in cell division remains poorly understood. Here, we identify a role for IPIP27 in mediating cellular PtdIns(4,5)P homeostasis. IPIP27 scaffolds the inositol phosphatase oculocerebrorenal syndrome of Lowe (OCRL) by coupling it to endocytic BAR domain proteins. Loss of IPIP27 causes accumulation of PtdIns(4,5)P on aberrant endomembrane vacuoles, mislocalization of the cytokinetic machinery, and extensive cortical membrane blebbing. This phenotype is observed in Drosophila and human cells and can result in cytokinesis failure. We have therefore identified IPIP27 as a key modulator of cellular PtdIns(4,5)P homeostasis required for normal cytokinesis. The results indicate that scaffolding of inositol phosphatase activity is critical for maintaining PtdIns(4,5)P homeostasis and highlight a critical role for this process in cell division.
Topics: Animals; Cell Line; Cytokinesis; Drosophila melanogaster; HeLa Cells; Homeostasis; Humans; Oculocerebrorenal Syndrome; Phosphatidylinositols
PubMed: 30799246
DOI: 10.1016/j.cub.2019.01.043 -
IUBMB Life Aug 2006Phosphoinositide signaling molecules control cellular growth, proliferation and differentiation, intracellular vesicle trafficking, and cytoskeletal rearrangement. The... (Review)
Review
Phosphoinositide signaling molecules control cellular growth, proliferation and differentiation, intracellular vesicle trafficking, and cytoskeletal rearrangement. The inositol polyphosphate 5-phosphatase family remove the D-5 position phosphate from PtdIns(3,4,5)P3, PtdIns(4,5)P2 and PtdIns(3,5)P2 forming PtdIns(3,4)P2, PtdIns(4)P and PtdIns(3)P respectively. This enzyme family, comprising ten mammalian members, exhibit seemingly non-redundant functions including the regulation of synaptic vesicle recycling, hematopoietic cell function and insulin signaling. Here we highlight recently established insights into the functions of two well characterized 5-phosphatases OCRL and SHIP2, which have been the subject of extensive functional studies, and the characterization of recently identified members, SKIP and PIPP, in order to highlight the diverse and complex functions of this enzyme family.
Topics: Animals; Humans; Inositol Polyphosphate 5-Phosphatases; Isoenzymes; Models, Biological; Oculocerebrorenal Syndrome; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Protein Structure, Tertiary; Signal Transduction
PubMed: 16916781
DOI: 10.1080/15216540600871159 -
CEN Case Reports May 2020The oculocerebrorenal disorder of Lowe syndrome is an X-linked mutation in the gene oculocerebrorenal syndrome of Lowe 1 (OCRL), characterized by the triad of congenital...
The oculocerebrorenal disorder of Lowe syndrome is an X-linked mutation in the gene oculocerebrorenal syndrome of Lowe 1 (OCRL), characterized by the triad of congenital cataracts, severe intellectual impairment, and renal tubular dysfunction. Manifestations of phenotype in female carriers and patients are extremely rare. We present a female case with congenital cataracts, severe intellectual impairment, sensorineural hearing loss, and renal tubular dysfunction as Lowe syndrome. A 9-year-old Japanese girl visited our hospital due to prolonged proteinuria. Her renal biopsy revealed diffuse mesangium proliferation, sclerosis and dilatation of renal tubules, and mild IgA deposition in the mesangial region. Furthermore, she had congenital cataracts, severe intellectual impairment, and sensorineural hearing loss. Genetic screening did not identify mutations of the ORCL gene encoding inositol polyphosphate 5-phosphatase (IPP-5P) (46 XX, female). However, we found the reduction of enzyme activity of IPP-5P to 50% of the normal value. Furthermore, her renal function had deteriorated to renal failure within a decade. Finally, she received peritoneal dialysis and renal transplantation. We present the oculocerebrorenal phenotype of Lowe syndrome in a female patient with reduced activity of IPP-5P without OCRL gene mutation.
Topics: Asian People; Cataract; Child; Disease Progression; Female; Glomerulonephritis, IGA; Hearing Loss, Sensorineural; Humans; Inositol Polyphosphate 5-Phosphatases; Intellectual Disability; Kidney Transplantation; Kidney Tubules, Proximal; Mutation; Oculocerebrorenal Syndrome; Peritoneal Dialysis; Phenotype; Proteinuria; Renal Insufficiency; Severity of Illness Index
PubMed: 31707643
DOI: 10.1007/s13730-019-00434-z -
Zhongguo Dang Dai Er Ke Za Zhi =... Apr 2014Oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked recessive disorder. This study investigated the history of a Chinese family with OCRL and used direct DNA...
Oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked recessive disorder. This study investigated the history of a Chinese family with OCRL and used direct DNA sequencing to screen all exons of OCRL gene for mutations. A missense mutation (1736 A→G) in exon 15 was revealed, which resulted in the change of His (H) 507 to Arg (R). The patient's mother was the carrier of the heterozygous mutation in X-chromosome. To our knowledge, H507R mutation in OCRL gene has not been reported in Chinese people.
Topics: DNA Mutational Analysis; Humans; Infant; Male; Mutation, Missense; Oculocerebrorenal Syndrome; Phosphoric Monoester Hydrolases
PubMed: 24750831
DOI: No ID Found