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2.
Cell Commun Signal ; 21(1): 256, 2023 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-38049819

RESUMO

BACKGROUND: This study aimed to identify an orcl1 mutation in a patient with Dent-2 Disease and investigate the underlying mechanisms. METHODS: The ocrl1 mutation was identified through exome sequencing. Knockdown of orcl1 and overexpression of the orcl1 mutant were performed in HK-2 and MPC5 cells to study its function, while flow cytometry measured reactive oxygen species (ROS), phosphatidylserine levels, and cell apoptosis. Scanning electron microscopy observed crystal adhesion, while transmission electron microscopy examined kidney tissue pathology. Laser scanning confocal microscopy was used to examine endocytosis, and immunohistochemical and immunofluorescence assays detected protein expression. Additionally, podocyte-specific orcl1 knockout mice were generated to investigate the role of orcl1 in vivo. RESULTS: We identified a mutation resulting in the replacement of Histidine with Arginine at position 318 (R318H) in ocrl1 in the proband. orcl1 was widely expressed in the kidney. In vitro experiments showed that knockdown of orcl1 and overexpression of ocrl1 mutant increased ROS, phosphatidylserine exocytosis, crystal adhesion, and cell apoptosis in HK-2 cells. Knockdown of orcl1 in podocytes reduced endocytosis and disrupted the cell cycle while increasing cell migration. In vivo studies in mice showed that conditional deletion of orcl1 in podocytes caused glomerular dysfunction, including proteinuria and fibrosis. CONCLUSION: This study identified an R318H mutation in orcl1 in a patient with Dent-2 Disease. This mutation may contribute to renal injury by promoting ROS production and inducing cell apoptosis in tubular cells, while disrupting endocytosis and the cell cycle, and promoting cell migration of podocytes. Video Abstract.


Assuntos
Síndrome Oculocerebrorrenal , Podócitos , Humanos , Animais , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Fosfatidilserinas/metabolismo , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/metabolismo , Endocitose , Apoptose , Ciclo Celular
3.
Oral Surg Oral Med Oral Pathol Oral Radiol ; 136(6): e171-e176, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37891120

RESUMO

Lowe syndrome (LS) is a rare disease (1:500,000) with X-linked recessive inheritance involving the kidneys, eyes, and nervous system. A Mexican 25-year-old male patient presented for diagnosis of multiple radiolucent lesions observed on routine radiographic examination. General aspects revealed cognitive delay, eye alterations, and kidney involvement, which support the diagnosis of LS. Radiolucent well-delimited lesions were observed in both mandibular angle and symphysis. Under general anesthesia, incisional biopsy and decompression were performed. Histological aspects led to diagnosing odontogenic keratocyst (OKC) for all lesions. The lesions in the right and left mandibular angles were decompressed, and the symphyseal lesion was enucleated. A 2-month follow-up shows the bone healing process. There are few reports detailing oral findings in LS. Here, we reported the first case of multiple OKC in a patient with LS. In addition, we performed a literature review on odontogenic lesions in patients affected by LS.


Assuntos
Síndrome Oculocerebrorrenal , Cistos Odontogênicos , Tumores Odontogênicos , Masculino , Humanos , Adulto , Cistos Odontogênicos/diagnóstico por imagem , Cistos Odontogênicos/cirurgia , Cistos Odontogênicos/patologia , Mandíbula/patologia , Diagnóstico Diferencial
4.
J Biol Chem ; 299(6): 104812, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37172724

RESUMO

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)P2] 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)P2 hydrolysis by phosphoinositide phospholipase C ß3 and uncontrolled Ca2+ release from the endoplasmic reticulum. We propose OCRL1 deletion leads to accumulation of PI(4,5)P2 in the PM, disrupting the normal Ca2+ oscillation pattern in the cytosol and leading to mitochondrial Ca2+ 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)P2 availability in T-ALL cells. Our findings also raise the possibility of targeting OCRL1 to treat T-ALL disease.


Assuntos
Membrana Celular , Fosfatidilinositol 4,5-Difosfato , Monoéster Fosfórico Hidrolases , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Linfócitos T , Humanos , Membrana Celular/metabolismo , Sobrevivência Celular , Hidrólise , Síndrome Oculocerebrorrenal/enzimologia , Síndrome Oculocerebrorrenal/genética , Fosfatidilinositol 4,5-Difosfato/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Linfócitos T/citologia , Linfócitos T/imunologia , Monoéster Fosfórico Hidrolases/biossíntese , Monoéster Fosfórico Hidrolases/deficiência , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Complexo de Golgi/metabolismo , Ligantes , Transporte Proteico , Sinalização do Cálcio , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Citosol/metabolismo
5.
Biomolecules ; 13(4)2023 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-37189363

RESUMO

Lowe Syndrome (LS) is a condition due to mutations in the OCRL1 gene, characterized by congenital cataracts, intellectual disability, and kidney malfunction. Unfortunately, patients succumb to renal failure after adolescence. This study is centered in investigating the biochemical and phenotypic impact of patient's OCRL1 variants (OCRL1VAR). Specifically, we tested the hypothesis that some OCRL1VAR are stabilized in a non-functional conformation by focusing on missense mutations affecting the phosphatase domain, but not changing residues involved in binding/catalysis. The pathogenic and conformational characteristics of the selected variants were evaluated in silico and our results revealed some OCRL1VAR to be benign, while others are pathogenic. Then we proceeded to monitor the enzymatic activity and function in kidney cells of the different OCRL1VAR. Based on their enzymatic activity and presence/absence of phenotypes, the variants segregated into two categories that also correlated with the severity of the condition they induce. Overall, these two groups mapped to opposite sides of the phosphatase domain. In summary, our findings highlight that not every mutation affecting the catalytic domain impairs OCRL1's enzymatic activity. Importantly, data support the inactive-conformation hypothesis. Finally, our results contribute to establishing the molecular and structural basis for the observed heterogeneity in severity/symptomatology displayed by patients.


Assuntos
Síndrome Oculocerebrorrenal , Humanos , Síndrome Oculocerebrorrenal/genética , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/química , Mutação , Mutação de Sentido Incorreto , Fenótipo
6.
Am J Case Rep ; 24: e938248, 2023 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-36959724

RESUMO

BACKGROUND Lowe syndrome, also known as oculocerebrorenal syndrome, is a rare genetic condition caused by an X-linked mutation of the OCRL1 gene, with an estimated prevalence in the general population of approximately 1 in 500 000. It is a multisystem disorder most commonly affecting the eyes, central nervous system, and kidneys. These commonly manifest as congenital cataracts, intellectual disability, and proximal renal dysfunction (Fanconi-type). Epidermal lesions are an uncommon manifestation of this condition, and the association is not completely understood. CASE REPORT Here we present a case of a 9-year-old boy with Lowe syndrome who presented with multiple cystic masses found in the perianal region. An excision was then performed to remove the masses and found that the lesions were epidermal cysts, which are infrequently found in Lowe syndrome. After excision, the patient recovered uneventfully without complications. CONCLUSIONS While epidermal cysts are an uncommon manifestation that have been documented, our case remains unique given the location and associated symptoms of the lesions. At presentation, the constellation of pain and perianal masses was concerning for a malignant etiology. However, after diagnostic imaging was performed, these lesions were found to be epidermal cysts, an infrequent manifestation of Lowe syndrome. Few previous case reports described cystic lesions in association with Lowe syndrome, and none, to our knowledge, have described multiple symptomatic perianal lesions. This case is important to consider because epidermal cystic lesions can be found with this presentation and should be considered on differential diagnoses for dermatologic findings in Lowe syndrome patients.


Assuntos
Cisto Epidérmico , Deficiência Intelectual , Síndrome Oculocerebrorrenal , Síndrome WAGR , Masculino , Humanos , Criança , Síndrome Oculocerebrorrenal/complicações , Síndrome Oculocerebrorrenal/diagnóstico , Síndrome Oculocerebrorrenal/genética , Cisto Epidérmico/complicações , Cisto Epidérmico/diagnóstico , Cisto Epidérmico/cirurgia , Mutação , Deficiência Intelectual/complicações , Síndrome WAGR/complicações
7.
World J Pediatr ; 19(7): 619-634, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36729281

RESUMO

BACKGROUND: Fanconi-Debré-de Toni syndrome (also known as Fanconi renotubular syndrome, or FRST) profoundly increased the understanding of the functions of the proximal convoluted tubule (PCT) and provided important insights into the pathophysiology of several kidney diseases and drug toxicities. DATA SOURCES: We searched Pubmed and Scopus databases to find relevant articles about FRST. This review article focuses on the physiology of the PCT, as well as on the physiopathology of FRST in children, its diagnosis, and treatment. RESULTS: FRST encompasses a wide variety of inherited and acquired PCT alterations that lead to impairment of PCT reabsorption. In children, FRST often presents as a secondary feature of systemic disorders that impair energy supply, such as Lowe's syndrome, Dent's disease, cystinosis, hereditary fructose intolerance, galactosemia, tyrosinemia, Alport syndrome, and Wilson's disease. Although rare, congenital causes of FRST greatly impact the morbidity and mortality of patients and impose diagnostic challenges. Furthermore, its treatment is diverse and considers the ability of the clinician to identify the correct etiology of the disease. CONCLUSION: The early diagnosis and treatment of pediatric patients with FRST improve the prognosis and the quality of life.


Assuntos
Cistinose , Síndrome de Fanconi , Nefropatias , Síndrome Oculocerebrorrenal , Humanos , Criança , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/genética , Síndrome de Fanconi/terapia , Qualidade de Vida , Cistinose/complicações , Síndrome Oculocerebrorrenal/complicações
8.
Br J Haematol ; 200(1): 87-99, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36176266

RESUMO

Lowe syndrome (LS) is a rare, X-linked disorder characterised by numerous symptoms affecting the brain, the eyes, and the kidneys. It is caused by mutations in the oculocerebrorenal syndrome of Lowe (OCRL) protein, a 5-phosphatase localised in different cellular compartments that dephosphorylates phosphatidylinositol-4,5-bisphosphate into phosphatidylinositol-4-monophosphate. Some patients with LS also have bleeding disorders, with normal to low platelet (PLT) count and impaired PLT function. However, the mechanism of PLT dysfunction in patients with LS is not completely understood. The main function of PLTs is to activate upon vessel wall injury and stop the bleeding by clot formation. PLT activation is accompanied by a shape change that is a result of massive cytoskeletal rearrangements. Here, we show that OCRL-inhibited human PLTs do not fully spread, form mostly filopodia, and accumulate actin nodules. These nodules co-localise with ARP2/3 subunit p34, vinculin, and sorting nexin 9. Furthermore, OCRL-inhibited PLTs have a retained microtubular coil with high levels of acetylated tubulin. Also, myosin light chain phosphorylation is decreased upon OCRL inhibition, without impaired degranulation or integrin activation. Taken together, these results suggest that OCRL contributes to cytoskeletal rearrangements during PLT activation that could explain mild bleeding problems in patients with LS.


Assuntos
Síndrome Oculocerebrorrenal , Síndrome WAGR , Humanos , Síndrome Oculocerebrorrenal/genética , Actinas , Rim/metabolismo , Mutação
9.
Genet Res (Camb) ; 2022: 1473260, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35919034

RESUMO

Background: Both Lowe syndrome and Dent-2 disease are caused by variants in the OCRL gene. However, the reason why patients with similar OCRL gene mutations presented with different phenotypes remains uncertain. Methods: Children with hemizygous pathogenic or likely pathogenic variants in OCRL 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 (Χ2 = 12.662; P < 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%; Χ2 = 14.922; P < 0.001). Conclusions: Truncating mutations of the OCRL 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 OCRL 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 OCRL variants and genetic counseling. Furthermore, a large international study would be necessary to illustrate the genotype-phenotype correlation in patients with OCRL mutations.


Assuntos
Síndrome Oculocerebrorrenal , Estudos de Coortes , Estudos de Associação Genética , Humanos , Mutação , Síndrome Oculocerebrorrenal/genética , Monoéster Fosfórico Hidrolases/genética
10.
J Cell Sci ; 135(18)2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-35979861

RESUMO

Endocytosis allows cells to internalise a wide range of molecules from their environment and to maintain their plasma membrane composition. It is vital during development and for maintenance of tissue homeostasis. The ability to visualise endocytosis in vivo requires suitable assays to monitor the process. Here, we describe imaging-based assays to visualise endocytosis in the neuroepithelium of living zebrafish embryos. Injection of fluorescent tracers into the brain ventricles followed by live imaging was used to study fluid-phase or receptor-mediated endocytosis, for which we used receptor-associated protein (RAP, encoded by Lrpap1) as a ligand for low-density lipoprotein receptor-related protein (LRP) receptors. Using dual-colour imaging combined with expression of endocytic markers, it is possible to track the progression of endocytosed tracers and to monitor trafficking dynamics. Using these assays, we reveal a role for the Lowe syndrome protein Ocrl in endocytic trafficking within the neuroepithelium. We also found that the RAP-binding receptor Lrp2 (encoded by lrp2a) appears to contribute only partially to neuroepithelial RAP endocytosis. Altogether, our results provide a basis to track endocytosis within the neuroepithelium in vivo and support a role for Ocrl in this process. This article has an associated First Person interview with the first author of the paper.


Assuntos
Síndrome Oculocerebrorrenal , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Proteínas de Transporte/metabolismo , Endocitose , Ligantes , Lipoproteínas LDL/metabolismo , Peixe-Zebra/metabolismo
11.
J Med Genet ; 59(12): 1171-1178, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35803701

RESUMO

BACKGROUND: Lowe syndrome (LS) is an X linked disease caused by pathogenic variants in the OCRL 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 OCRL 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. OCRL is expressed in human and mouse hypothalami, and in hypothalamic cell clusters expressing Ghrh, Sst, Oxt, Pomc and pituitary cells expressing Gh and Prl. 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 OCRL in the hypothalamus and the pituitary.


Assuntos
Catarata , Síndrome Oculocerebrorrenal , Criança , Masculino , Animais , Camundongos , Feminino , Humanos , Lactente , Pré-Escolar , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/metabolismo , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Fenótipo , Catarata/genética , Encéfalo/metabolismo
13.
CEN Case Rep ; 11(3): 366-370, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35098431

RESUMO

A 7-year-old boy visited our hospital for a detailed examination of proteinuria identified in a school urinary test. He had short stature, misaligned teeth, and mild intellectual disability. A urinary examination identified mild proteinuria and extremely high levels of beta-2 microglobulin. On blood examination, his protein, albumin, and creatinine levels were found to be normal; however, his lactate dehydrogenase and creatinine phosphokinase levels were slightly elevated. Upon histological examination, no abnormalities in glomeruli or tubules were found. Considering these results, we diagnosed our patient with Dent disease type 2 (DD2). Although the whole exome sequencing revealed large deletion of OCRL, which was seen only in Lowe syndrome and not in DD2 previously, our final diagnosis for the patient is DD2. A phenotypic continuum exists between Dent disease and Lowe syndrome, and several factors modify the phenotypes caused by defects in OCRL. Although patients have thus far been diagnosed with DD2 or Lowe syndrome on the basis of their symptoms, accumulation and analysis of cases with OCRL defects may hereafter enable more accurate diagnoses.


Assuntos
Doença de Dent , Síndrome Oculocerebrorrenal , Creatinina , Doença de Dent/genética , Humanos , Masculino , Mutação , Síndrome Oculocerebrorrenal/genética , Monoéster Fosfórico Hidrolases/genética , Proteinúria/diagnóstico , Instituições Acadêmicas
14.
Biol Open ; 11(1)2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-35023542

RESUMO

Human brain development is a complex process where multiple cellular and developmental events are coordinated to generate normal structure and function. Alteration in any of these events can impact brain development, manifesting clinically as neurodevelopmental disorders. Human genetic disorders of lipid metabolism often present with features of altered brain function. Lowe syndrome (LS) is an X-linked recessive disease with features of altered brain function. LS results from mutations in OCRL1, which encodes a phosphoinositide 5-phosphatase enzyme. However, the cellular mechanisms by which loss of OCRL1 leads to brain defects remain unknown. Human brain development involves several cellular and developmental features not conserved in other species and understanding such mechanisms remains a challenge. Rodent models of LS have been generated but failed to recapitulate features of the human disease. Here we describe the generation of human stem cell lines from LS patients. Further, we present biochemical characterization of lipid metabolism in patient cell lines and demonstrate their use as a 'disease-in-a-dish' model for understanding the mechanism by which loss of OCRL1 leads to altered cellular and physiological brain development. This article has an associated First Person interview with the first author of the paper.


Assuntos
Síndrome Oculocerebrorrenal , Encéfalo/metabolismo , Linhagem Celular , Humanos , Mutação , Síndrome Oculocerebrorrenal/genética , Células-Tronco/metabolismo
15.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 39(1): 56-59, 2022 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-34964968

RESUMO

OBJECTIVE: To explore the genotype-phenotype correlation of a Chinese pedigree affected with Lowe syndrome. METHODS: Whole exome sequencing (WES) and Sanger sequencing were carried out for the proband and members of his pedigree. RESULTS: The proband, a 3-year-and-5-month-old male, presented with multiple anomalies including congenital cataract, glaucoma, brain dysplasia, renal dysfunction and cognitive impairment. WES revealed that he has harbored a novel hemizygous missense variant of the OCRL gene, namely NM_000276.3: c.1255T>C (p.Trp419Arg) (GRCh37/hg19), which was derived from his unaffected mother. The same variant was not found in his elder brother who was healthy. The variant was predicted to be pathogenic according to ACMG/AMP guideline. Compared with previously reported cases of Lowe syndrome, our patient has displayed rare features including corpus callosum dysplasia, reduction of white matter, cerebral hypoplasia, laryngomalacia, sebaceous cyst, recurrent eczema, cryptorchidism, hypoglycemia and irritability. CONCLUSION: Above finding has expanded the mutational spectrum of the OCRL gene, enriched clinical features of Lowe syndrome, and enabled genetic counseling for this pedigree.


Assuntos
Síndrome Oculocerebrorrenal , Idoso , China , Estudos de Associação Genética , Humanos , Lactente , Masculino , Mutação , Linhagem , Monoéster Fosfórico Hidrolases/genética , Sequenciamento do Exoma
16.
Hum Mol Genet ; 31(8): 1183-1196, 2022 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-34673953

RESUMO

Endocytosis is a fundamentally important process through which material is internalized into cells from the extracellular environment. In the renal proximal tubule, endocytosis of the abundant scavenger receptor megalin and its co-receptor cubilin play a vital role in retrieving low molecular weight proteins from the renal filtrate. Although we know much about megalin and its ligands, the machinery and mechanisms by which the receptor is trafficked through the endosomal system remain poorly defined. In this study, we show that inositol phosphatase interacting protein of 27 kDa (Ipip27A), an interacting partner of the Lowe syndrome protein oculocerebrorenal syndrome of Lowe (OCRL), is required for endocytic traffic of megalin within the proximal renal tubule of zebrafish larvae. Knockout of Ipip27A phenocopies the endocytic phenotype seen upon loss of OCRL, with a deficit in uptake of both fluid-phase and protein cargo, which is accompanied by a reduction in megalin abundance and altered endosome morphology. Rescue and co-depletion experiments indicate that Ipip27A functions together with OCRL to support proximal tubule endocytosis. The results therefore identify Ipip27A as a new player in endocytic traffic in the proximal tubule in vivo and support the view that defective endocytosis underlies the renal tubulopathy in Lowe syndrome and Dent-2 disease.


Assuntos
Síndrome Oculocerebrorrenal , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Endocitose/genética , Endossomos/genética , Endossomos/metabolismo , Feminino , Humanos , Fosfatos de Inositol/metabolismo , Túbulos Renais Proximais/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/metabolismo , Monoéster Fosfórico Hidrolases/genética , Proteínas/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
17.
Nephrol Dial Transplant ; 37(2): 262-270, 2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-34586410

RESUMO

BACKGROUND: Although Lowe syndrome and Dent disease-2 are caused by Oculocerebrorenal syndrome of Lowe (OCRL) mutations, their clinical severities differ substantially and their molecular mechanisms remain unclear. Truncating mutations in OCRL exons 1-7 lead to Dent disease-2, whereas those in exons 8-24 lead to Lowe syndrome. Herein we identified the mechanism underlying the action of novel OCRL protein isoforms. METHODS: Messenger RNA samples extracted from cultured urine-derived cells from a healthy control and a Dent disease-2 patient were examined to detect the 5' end of the OCRL isoform. For protein expression and functional analysis, vectors containing the full-length OCRL transcripts, the isoform transcripts and transcripts with truncating mutations detected in Lowe syndrome and Dent disease-2 patients were transfected into HeLa cells. RESULTS: We successfully cloned the novel isoform transcripts from OCRL exons 6-24, including the translation-initiation codons present in exon 8. In vitro protein-expression analysis detected proteins of two different sizes (105 and 80 kDa) translated from full-length OCRL, whereas only one protein (80 kDa) was found from the isoform and Dent disease-2 variants. No protein expression was observed for the Lowe syndrome variants. The isoform enzyme activity was equivalent to that of full-length OCRL; the Dent disease-2 variants retained >50% enzyme activity, whereas the Lowe syndrome variants retained <20% activity. CONCLUSIONS: We elucidated the molecular mechanism underlying the two different phenotypes in OCRL-related diseases; the functional OCRL isoform translated starting at exon 8 was associated with this mechanism.


Assuntos
Doença de Dent , Síndrome Oculocerebrorrenal , Monoéster Fosfórico Hidrolases , Doença de Dent/diagnóstico , Doença de Dent/genética , Células HeLa , Humanos , Mutação/genética , Síndrome Oculocerebrorrenal/diagnóstico , Síndrome Oculocerebrorrenal/genética , Fenótipo , Monoéster Fosfórico Hidrolases/genética , Isoformas de Proteínas/genética
18.
Genes (Basel) ; 12(10)2021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34680992

RESUMO

Dent disease is a rare X-linked renal tubulopathy due to CLCN5 and OCRL (DD2) mutations. OCRL mutations also cause Lowe syndrome (LS) involving the eyes, brain and kidney. DD2 is frequently described as a mild form of LS because some patients may present with extra-renal symptoms (ESs). Since DD2 is a rare disease and there are a low number of reported cases, it is still unclear whether it has a clinical picture distinct from LS. We retrospectively analyzed the phenotype and genotype of our cohort of 35 DD2 males and reviewed all published DD2 cases. We analyzed the distribution of mutations along the OCRL gene and evaluated the type and frequency of ES according to the type of mutation and localization in OCRL protein domains. The frequency of patients with at least one ES was 39%. Muscle findings are the most common ES (52%), while ocular findings are less common (11%). Analysis of the distribution of mutations revealed (1) truncating mutations map in the PH and linker domain, while missense mutations map in the 5-phosphatase domain, and only occasionally in the ASH-RhoGAP module; (2) five OCRL mutations cause both DD2 and LS phenotypes; (3) codon 318 is a DD2 mutational hot spot; (4) a correlation was found between the presence of ES and the position of the mutations along OCRL domains. DD2 is distinct from LS. The mutation site and the mutation type largely determine the DD2 phenotype.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Pleiotropia Genética/genética , Nefrolitíase/genética , Síndrome Oculocerebrorrenal/genética , Monoéster Fosfórico Hidrolases/genética , Adolescente , Variação Biológica da População/genética , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/epidemiologia , Genótipo , Humanos , Rim/metabolismo , Rim/patologia , Masculino , Mutação de Sentido Incorreto/genética , Nefrolitíase/diagnóstico , Nefrolitíase/epidemiologia , Síndrome Oculocerebrorrenal/diagnóstico , Síndrome Oculocerebrorrenal/epidemiologia , Fenótipo
19.
BMC Med Genomics ; 14(1): 219, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488756

RESUMO

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.


Assuntos
Síndrome Oculocerebrorrenal
20.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069732

RESUMO

Lowe syndrome and Dent II disease are X-linked monogenetic diseases characterised by a renal reabsorption defect in the proximal tubules and caused by mutations in the OCRL gene, which codes for an inositol-5-phosphatase. The life expectancy of patients suffering from Lowe syndrome is largely reduced because of the development of chronic kidney disease and related complications. There is a need for physiological human in vitro models for Lowe syndrome/Dent II disease to study the underpinning disease mechanisms and to identify and characterise potential drugs and drug targets. Here, we describe a proximal tubule organ on chip model combining a 3D tubule architecture with fluid flow shear stress that phenocopies hallmarks of Lowe syndrome/Dent II disease. We demonstrate the high suitability of our in vitro model for drug target validation. Furthermore, using this model, we demonstrate that proximal tubule cells lacking OCRL expression upregulate markers typical for epithelial-mesenchymal transition (EMT), including the transcription factor SNAI2/Slug, and show increased collagen expression and deposition, which potentially contributes to interstitial fibrosis and disease progression as observed in Lowe syndrome and Dent II disease.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Túbulos Renais Proximais/metabolismo , Nefrolitíase/metabolismo , Síndrome Oculocerebrorrenal/metabolismo , Humanos , Dispositivos Lab-On-A-Chip , Modelos Biológicos , Mutação , Fenótipo , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo
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