RESUMO
Lowe syndrome (LS) is an oculocerebrorenal syndrome of Lowe (OCRL1) genetic disorder resulting in a defect of the OCRL protein, a phosphatidylinositol-4,5-bisphosphate 5-phosphatase containing various domains including a Rho GTPase-activating protein (RhoGAP) homology domain catalytically inactive. We previously reported surgery-associated bleeding in patients with LS, suggestive of platelet dysfunction, accompanied with a mild thrombocytopenia in several patients. To decipher the role of OCRL in platelet functions and in megakaryocyte (MK) maturation, we conducted a case-control study on 15 patients with LS (NCT01314560). While all had a drastically reduced expression of OCRL, this deficiency did not affect platelet aggregability, but resulted in delayed thrombus formation on collagen under flow conditions, defective platelet spreading on fibrinogen and impaired clot retraction. We evidenced alterations of the myosin light chain phosphorylation (P-MLC), with defective Rac1 activity and, inversely, elevated active RhoA. Altered cytoskeleton dynamics was also observed in cultured patient MKs showing deficient proplatelet extension with increased P-MLC that was confirmed using control MKs transfected with OCRL-specific small interfering(si)RNA (siOCRL). Patients with LS also had an increased proportion of circulating barbell-shaped proplatelets. Our present study establishes that a deficiency of the OCRL protein results in a defective actomyosin cytoskeleton reorganisation in both MKs and platelets, altering both thrombopoiesis and some platelet responses to activation necessary to ensure haemostasis.
Assuntos
Plaquetas/citologia , Megacariócitos/citologia , Síndrome Oculocerebrorrenal/genética , Monoéster Fosfórico Hidrolases/fisiologia , Trombopoese/fisiologia , Actomiosina/análise , Adolescente , Adulto , Anemia/etiologia , Coagulação Sanguínea , Plaquetas/ultraestrutura , Estudos de Casos e Controles , Forma Celular , Criança , Colágeno , Citoesqueleto/ultraestrutura , Feminino , Inativação Gênica , Humanos , Masculino , Megacariócitos/ultraestrutura , Pessoa de Meia-Idade , Mutação , Cadeias Leves de Miosina/metabolismo , Síndrome Oculocerebrorrenal/sangue , Síndrome Oculocerebrorrenal/patologia , Monoéster Fosfórico Hidrolases/deficiência , Monoéster Fosfórico Hidrolases/genética , Fosforilação , Domínios Proteicos , Processamento de Proteína Pós-Traducional , RNA Interferente Pequeno/genética , Transdução de Sinais , Trombocitopenia/etiologia , Adulto JovemRESUMO
The oculocerebrorenal (OCRL) syndrome, also known as Lowe syndrome (LS), is an X-linked recessive disorder that predominantly affects males and is characterized by growth and mental retardation, congenital cataract and renal Fanconi syndrome. OCRL1 is the gene responsible for LS and encodes an inositol polyphosphate-5-phosphatase. We report a male child from North India, with LS with missense mutation in exon 14 of the OCRL gene.
Assuntos
Mutação de Sentido Incorreto/genética , Síndrome Oculocerebrorrenal/genética , Monoéster Fosfórico Hidrolases/genética , Adolescente , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Mãos/diagnóstico por imagem , Mãos/patologia , Humanos , Índia , Masculino , Síndrome Oculocerebrorrenal/diagnóstico por imagem , Síndrome Oculocerebrorrenal/patologia , Pelve/diagnóstico por imagem , Pelve/patologiaRESUMO
The tumor suppressor PTEN dephosphorylates PtdIns(3,4,5)P3 into PtdIns(4,5)P2 Here, we make the unexpected discovery that in Drosophila melanogaster PTEN reduces PtdIns(4,5)P2 levels on endosomes, independently of its phosphatase activity. This new PTEN function requires the enzymatic action of dPLCXD, an atypical phospholipase C. Importantly, we discovered that this novel PTEN/dPLCXD pathway can compensate for depletion of dOCRL, a PtdIns(4,5)P2 phosphatase. Mutation of OCRL1, the human orthologue of dOCRL, causes oculocerebrorenal Lowe syndrome, a rare multisystemic genetic disease. Both OCRL1 and dOCRL loss have been shown to promote accumulation of PtdIns(4,5)P2 on endosomes and cytokinesis defects. Here, we show that PTEN or dPLCXD overexpression prevents these defects. In addition, we found that chemical activation of this pathway restores normal cytokinesis in human Lowe syndrome cells and rescues OCRL phenotypes in a zebrafish Lowe syndrome model. Our findings identify a novel PTEN/dPLCXD pathway that controls PtdIns(4,5)P2 levels on endosomes. They also point to a potential new strategy for the treatment of Lowe syndrome.
Assuntos
Proteínas de Drosophila/genética , Síndrome Oculocerebrorrenal/genética , PTEN Fosfo-Hidrolase/genética , Monoéster Fosfórico Hidrolases/genética , Fosfolipases Tipo C/genética , Animais , Citocinese/genética , Modelos Animais de Doenças , Drosophila melanogaster/genética , Endossomos/genética , Endossomos/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Síndrome Oculocerebrorrenal/metabolismo , Síndrome Oculocerebrorrenal/patologia , Fosfatidilinositol 4,5-Difosfato/genética , Fosfatidilinositol 4,5-Difosfato/metabolismo , Fosfatos de Fosfatidilinositol/genética , Fosfatos de Fosfatidilinositol/metabolismo , Transdução de SinaisRESUMO
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)P2). 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.
Assuntos
Glaucoma/patologia , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/patologia , Monoéster Fosfórico Hidrolases/genética , Olho/patologia , Genótipo , Glaucoma/congênito , Glaucoma/genética , Humanos , Queratinócitos/metabolismo , Masculino , Mutação de Sentido Incorreto , Síndrome Oculocerebrorrenal/complicações , Linhagem , Fenótipo , Monoéster Fosfórico Hidrolases/química , Estrutura Terciária de Proteína , Deleção de SequênciaRESUMO
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.
Assuntos
Síndrome Oculocerebrorrenal/terapia , Adolescente , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 11 , Humanos , Lactente , Recém-Nascido , Biologia Molecular , Mutação , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/patologia , Síndrome WAGRRESUMO
Mutation of the inositol 5-phosphatase OCRL1 causes Lowe syndrome and Dent-2 disease. Loss of OCRL1 function perturbs several cellular processes, including membrane traffic, but the underlying mechanisms remain poorly defined. Here we show that OCRL1 is part of the membrane-trafficking machinery operating at the trans-Golgi network (TGN)/endosome interface. OCRL1 interacts via IPIP27A with the F-BAR protein pacsin 2. OCRL1 and IPIP27A localize to mannose 6-phosphate receptor (MPR)-containing trafficking intermediates, and loss of either protein leads to defective MPR carrier biogenesis at the TGN and endosomes. OCRL1 5-phosphatase activity, which is membrane curvature sensitive, is stimulated by IPIP27A-mediated engagement of OCRL1 with pacsin 2 and promotes scission of MPR-containing carriers. Our data indicate a role for OCRL1, via IPIP27A, in regulating the formation of pacsin 2-dependent trafficking intermediates and reveal a mechanism for coupling PtdIns(4,5)P2 hydrolysis with carrier biogenesis on endomembranes.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Animais , Células COS , Endocitose , Endossomos/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Células HEK293 , Células HeLa , Humanos , Inositol Polifosfato 5-Fosfatases , Nefrolitíase/genética , Nefrolitíase/metabolismo , Nefrolitíase/patologia , Proteínas do Tecido Nervoso/metabolismo , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/metabolismo , Síndrome Oculocerebrorrenal/patologia , Fosfatidilinositóis/biossíntese , Fosfatidilinositóis/metabolismo , Transporte Proteico , Receptor IGF Tipo 2/metabolismo , Rede trans-Golgi/metabolismoRESUMO
Phosphoinositide (PIP) lipids regulate many aspects of cell function in the nervous system including receptor signalling, secretion, endocytosis, migration and survival. Levels of PIPs such as PI4P, PI(4,5)P2 and PI(3,4,5)P3 are normally tightly regulated by phosphoinositide kinases and phosphatases. Deregulation of these biochemical pathways leads to lipid imbalances, usually on intracellular endosomal membranes, and these changes have been linked to a number of major neurological diseases including Alzheimer's, Parkinson's, epilepsy, stroke, cancer and a range of rarer inherited disorders including brain overgrowth syndromes, Charcot-Marie-Tooth neuropathies and neurodevelopmental conditions such as Lowe's syndrome. This article analyses recent progress in this area and explains how PIP lipids are involved, to varying degrees, in almost every class of neurological disease. This article is part of a Special Issue entitled Brain Lipids.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Charcot-Marie-Tooth/metabolismo , Epilepsia/metabolismo , Síndrome Oculocerebrorrenal/metabolismo , Doença de Parkinson/metabolismo , Fosfatidilinositóis/metabolismo , Acidente Vascular Cerebral/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Epilepsia/genética , Epilepsia/patologia , Expressão Gênica , Humanos , Mutação , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/patologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Transdução de Sinais , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologiaRESUMO
Phosphoinositides (PIs) are a group of key signaling and structural lipid molecules involved in a myriad of cellular processes. PI phosphatases, together with PI kinases, are responsible for the conversion of PIs between distinctive phosphorylation states. PI phosphatases are a large collection of enzymes that are evolved from at least two disparate ancestors. One group is distantly related to endonucleases, which apply divalent metal ions for phosphoryl transfer. The other group is related to protein tyrosine phosphatases, which contain a highly conserved active site motif Cys-X5-Arg (CX5R). In this review, we focus on structural insights to illustrate current understandings of the molecular mechanisms of each PI phosphatase family, with emphasis on their structural basis for substrate specificity determinants and catalytic mechanisms. This article is part of a Special Issue entitled Phosphoinositides.
Assuntos
Proteínas de Bactérias/química , Proteínas de Membrana/química , PTEN Fosfo-Hidrolase/química , Monoéster Fosfórico Hidrolases/química , Proteínas Tirosina Fosfatases não Receptoras/química , Bactérias/química , Bactérias/enzimologia , Proteínas de Bactérias/metabolismo , Biocatálise , Membrana Celular/química , Membrana Celular/metabolismo , Cristalografia por Raios X , Doenças Genéticas Ligadas ao Cromossomo X/enzimologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Inositol Polifosfato 5-Fosfatases , Isoenzimas/química , Isoenzimas/metabolismo , Proteínas de Membrana/metabolismo , Modelos Moleculares , Nefrolitíase/enzimologia , Nefrolitíase/genética , Nefrolitíase/patologia , Síndrome Oculocerebrorrenal/enzimologia , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/patologia , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositóis/química , Fosfatidilinositóis/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Especificidade por SubstratoRESUMO
Mutations in the inositol 5-phosphatase OCRL cause Lowe syndrome and Dent's disease. Although OCRL, a direct clathrin interactor, is recruited to late-stage clathrin-coated pits, clinical manifestations have been primarily attributed to intracellular sorting defects. Here we show that OCRL loss in Lowe syndrome patient fibroblasts impacts clathrin-mediated endocytosis and results in an endocytic defect. These cells exhibit an accumulation of clathrin-coated vesicles and an increase in U-shaped clathrin-coated pits, which may result from sequestration of coat components on uncoated vesicles. Endocytic vesicles that fail to lose their coat nucleate the majority of the numerous actin comets present in patient cells. SNX9, an adaptor that couples late-stage endocytic coated pits to actin polymerization and which we found to bind OCRL directly, remains associated with such vesicles. These results indicate that OCRL acts as an uncoating factor and that defects in clathrin-mediated endocytosis likely contribute to pathology in patients with OCRL mutations.
Assuntos
Clatrina/metabolismo , Invaginações Revestidas da Membrana Celular/metabolismo , Fibroblastos/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Células Cultivadas , Vesículas Revestidas por Clatrina/metabolismo , Vesículas Revestidas por Clatrina/ultraestrutura , Invaginações Revestidas da Membrana Celular/ultraestrutura , Endocitose/genética , Células HEK293 , Células HeLa , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Microscopia Confocal , Microscopia Eletrônica , Microscopia de Fluorescência/métodos , Mutação , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/metabolismo , Síndrome Oculocerebrorrenal/patologia , Fosfatos de Fosfatidilinositol/metabolismo , Monoéster Fosfórico Hidrolases/genética , Ligação Proteica , Proteoma/genética , Proteoma/metabolismo , Proteômica/métodos , Interferência de RNA , Nexinas de Classificação/genética , Nexinas de Classificação/metabolismoRESUMO
Inositol phosphatases are important regulators of cell signaling, polarity, and vesicular trafficking. Mutations in OCRL, an inositol polyphosphate 5-phosphatase, result in Oculocerebrorenal syndrome of Lowe, an X-linked recessive disorder that presents with congenital cataracts, glaucoma, renal dysfunction and mental retardation. INPP5B is a paralog of OCRL and shares similar structural domains. The roles of OCRL and INPP5B in the development of cataracts and glaucoma are not understood. Using ocular tissues, this study finds low levels of INPP5B present in human trabecular meshwork but high levels in murine trabecular meshwork. In contrast, OCRL is localized in the trabecular meshwork and Schlemm's canal endothelial cells in both human and murine eyes. In cultured human retinal pigmented epithelial cells, INPP5B was observed in the primary cilia. A functional role for INPP5B is revealed by defects in cilia formation in cells with silenced expression of INPP5B. This is further supported by the defective cilia formation in zebrafish Kupffer's vesicles and in cilia-dependent melanosome transport assays in inpp5b morphants. Taken together, this study indicates that OCRL and INPP5B are differentially expressed in the human and murine eyes, and play compensatory roles in cilia development.
Assuntos
Cílios/metabolismo , Síndrome Oculocerebrorrenal/patologia , Monoéster Fosfórico Hidrolases/metabolismo , Animais , Células Cultivadas , Cílios/patologia , Olho/metabolismo , Olho/patologia , Humanos , Imuno-Histoquímica , Camundongos , Microscopia de Fluorescência , Morfolinos/metabolismo , Síndrome Oculocerebrorrenal/metabolismo , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Monoéster Fosfórico Hidrolases/genética , Interferência de RNA , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Epitélio Pigmentado da Retina/citologia , Epitélio Pigmentado da Retina/metabolismo , Peixe-ZebraRESUMO
Phosphoinositide phosphatases comprise several large enzyme families with over 35 mammalian enzymes identified to date that degrade many phosphoinositide signals. Growth factor or insulin stimulation activates the phosphoinositide 3-kinase that phosphorylates phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P(2)] to form phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P(3)], which is rapidly dephosphorylated either by PTEN (phosphatase and tensin homologue deleted on chromosome 10) to PtdIns(4,5)P(2), or by the 5-phosphatases (inositol polyphosphate 5-phosphatases), generating PtdIns(3,4)P(2). 5-phosphatases also hydrolyze PtdIns(4,5)P(2) forming PtdIns(4)P. Ten mammalian 5-phosphatases have been identified, which regulate hematopoietic cell proliferation, synaptic vesicle recycling, insulin signaling, and embryonic development. Two 5-phosphatase genes, OCRL and INPP5E are mutated in Lowe and Joubert syndrome respectively. SHIP [SH2 (Src homology 2)-domain inositol phosphatase] 2, and SKIP (skeletal muscle- and kidney-enriched inositol phosphatase) negatively regulate insulin signaling and glucose homeostasis. SHIP2 polymorphisms are associated with a predisposition to insulin resistance. SHIP1 controls hematopoietic cell proliferation and is mutated in some leukemias. The inositol polyphosphate 4-phosphatases, INPP4A and INPP4B degrade PtdIns(3,4)P(2) to PtdIns(3)P and regulate neuroexcitatory cell death, or act as a tumor suppressor in breast cancer respectively. The Sac phosphatases degrade multiple phosphoinositides, such as PtdIns(3)P, PtdIns(4)P, PtdIns(5)P and PtdIns(3,5)P(2) to form PtdIns. Mutation in the Sac phosphatase gene, FIG4, leads to a degenerative neuropathy. Therefore the phosphatases, like the lipid kinases, play major roles in regulating cellular functions and their mutation or altered expression leads to many human diseases.
Assuntos
Neoplasias da Mama/enzimologia , Leucemia/enzimologia , Síndrome Oculocerebrorrenal/enzimologia , PTEN Fosfo-Hidrolase/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Diglicerídeos/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Inositol 1,4,5-Trifosfato/metabolismo , Inositol Polifosfato 5-Fosfatases , Leucemia/genética , Leucemia/patologia , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/patologia , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 4,5-Difosfato/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases , Monoéster Fosfórico Hidrolases/genética , Sistemas do Segundo MensageiroRESUMO
Cytokinesis is the last step of cell division that physically separates the daughter cells. As such, it ensures the proper inheritance of both nuclear and cytoplasmic contents. Accomplishment of cytokinesis in eukaryotes is dictated by several key events: establishment of the division plane, furrow ingression through contraction of an actomyosin ring and abscission via membrane fusion. Most mammalian somatic cells are diploid. Polyploidy can result from cytokinesis failure and may contribute to the development of pathologies such as cancer. However, polyploidy is essential for cellular differentiation and function in some contexts (eg hepatocytes, megakaryocytes and others). Consequently, the degree of ploidy and the achievement of cytokinesis must be tightly regulated throughout an organism and among different cell types. In this review we will highlight several examples of normal and pathological polyploidy, focusing on those caused by a controlled failure or dysregulation of cytokinesis, respectively. Last, we propose therapeutic routes to control cytokinesis to restore or block cell division.
Assuntos
Citocinese/genética , Ploidias , Aneuploidia , Feminino , Células Germinativas/patologia , Doenças Hematológicas/patologia , Hepatócitos/patologia , Humanos , Infertilidade Feminina/patologia , Degeneração Macular/patologia , Megacariócitos/patologia , Músculo Liso Vascular/patologia , Miócitos Cardíacos/patologia , Neoplasias/patologia , Neurofibromatose 2/patologia , Síndrome Oculocerebrorrenal/patologiaRESUMO
Abnormalities in the central nervous system and renal function are seen together in a variety of congenital syndromes. This Review examines the clinical presentation and the genetic basis of several such syndromes. The X-linked oculocerebrorenal syndrome of Lowe is characterized by developmental delay, blindness, renal tubular dysfunction, and progressive renal failure. This syndrome results from mutations in the OCRL gene, which encodes a phosphatase involved in endosomal trafficking. Mutations in OCRL also occur in Dent disease, which has a milder disease phenotype than Lowe syndrome. Patients with Joubert syndrome have cerebellar ataxia, pigmentary retinopathy, and nephronophthisis. Joubert syndrome is a genetically heterogeneous condition associated with mutations in at least five genes that encode ciliary proteins. Bardet-Biedl syndrome is a clinically variable condition associated with learning disabilities, progressive visual loss, obesity, polydactyly, hypogonadism, and cystic and fibrotic renal changes that can lead to renal failure. Most of the 12 genes mutated in Bardet-Biedl syndrome are also involved in ciliary function, as are the genes implicated in other 'ciliopathies' with similar phenotypes, including Meckel syndrome.
Assuntos
Síndrome de Bardet-Biedl/genética , Síndrome de Bardet-Biedl/patologia , Rim/anormalidades , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/patologia , HumanosRESUMO
Reports of corneal keloids are rare, with fewer than 80 cases published since the first case was documented in 1865. Keloids can be congenital or primary, but most often are associated with ocular surface injury or pathology. They have been reported in association with a number of congenital conditions, notably lowe's syndrome. Keloids are characterized histopathologically by a haphazard arrangement of fibroblasts, collagen bundles, and blood vessels. They have sometimes been confused with hypertrophic scars, but differ from such scars in that they may appear months or years after initial trauma and enlarge over time. The underlying cornea may be clear and uninvolved, or it may be opaque, depending on the primary pathology of the keloid. Treatment options include superficial keratectomy, lamellar or penetrating keratoplasty, and sclerokeratoplasty. The purpose of this review is to tabulate features of the reported corneal keloids, describing their etiologic, clinical, and histopathologic characteristics and discussing possible mechanisms of keloid formation.
Assuntos
Doenças da Córnea/patologia , Doenças da Córnea/cirurgia , Queloide/patologia , Queloide/cirurgia , Doenças da Córnea/complicações , Cirurgia da Córnea a Laser , Humanos , Queloide/etiologia , Ceratoplastia Penetrante , Síndrome Oculocerebrorrenal/complicações , Síndrome Oculocerebrorrenal/patologia , Síndrome Oculocerebrorrenal/cirurgiaRESUMO
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.
Assuntos
Síndrome Oculocerebrorrenal/metabolismo , Monoéster Fosfórico Hidrolases/genética , Actinas/metabolismo , Processamento Alternativo , Endossomos/metabolismo , Complexo de Golgi/enzimologia , Complexo de Golgi/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Modelos Biológicos , Mutação , Síndrome Oculocerebrorrenal/enzimologia , Síndrome Oculocerebrorrenal/genética , Síndrome Oculocerebrorrenal/patologia , Monoéster Fosfórico Hidrolases/química , Monoéster Fosfórico Hidrolases/metabolismo , Estrutura Terciária de Proteína , Proteínas rac de Ligação ao GTP/químicaRESUMO
We describe two cases of oculocerebrocutaneous syndrome (OCCS) or Delleman syndrome, characterized by congenital anomalies that involve the skin, orbit, and central nervous system (CNS). Complete MRI studies of the orbit, CNS and the entire spinal region must be performed in these cases. New MRI techniques can show cortical malformations, such as polymicrogyria, lissencephaly, or abnormal disposition of cortical sulci and gyri. Lesions can be bilateral or unilateral, as occurred in our patients. In one case, the ocular, skin, cerebral, and cerebellar lesions involved mainly the same side, whereas in the second case, all anomalies were generalized and the patient also showed skin hypopigmented lesions distributed bilaterally. Both patients show severe encephalopathy and Dandy-Walker malformation. One case is blind and shows generalized hydrocephalus, and the other one has vision through an eye, and has complete agenesis of the corpus callosum and severe disorder of neuronal migration and cortical organization with polymicrogyria and abnormal cortical sulci and gyri in a cerebral hemisphere. Our second case shows arachnoid cysts in both temporal, retrocerebellar, and spinal (D(8)-D(11)) regions, and lipoma in the pontomedullary and spinal (D(4)-D(7)) regions. The latter features correspond more to ECCL than to OCCS. The overlap between the two syndromes is unquestionable and it is possible that they constitute different manifestations of the same disorder.
Assuntos
Anormalidades do Olho/etiologia , Malformações do Sistema Nervoso/etiologia , Síndrome Oculocerebrorrenal/complicações , Anormalidades da Pele/etiologia , Anormalidades Múltiplas/etiologia , Criança , Pré-Escolar , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Malformações do Sistema Nervoso/patologia , Síndrome Oculocerebrorrenal/patologiaRESUMO
Clinicopathological features of the renal disease in Arima syndrome were studied in five autopsy cases. All cases showed insidious development of end-stage renal disease during childhood, preceded by polyuria/polydipsia, anemia, and growth failure. Decreased urinary concentrating ability and excessive sodium loss were the characteristic laboratory findings. Gross examination showed that both kidneys were small and showed multiple cysts of various sizes. The histological examinations revealed chronic sclerosing tubulo-interstitial nephropathy with cystic tubuli predominantly located at cortico-medullary areas. These observations suggest that the renal disease in Arima syndrome is in accordance with nephronophthisis both clinically and pathologically. Contrary to the previous literature which described that Arima syndrome can be distinguished from other Joubert-related cerebello-oculo-renal syndromes by its unique renal disease, i.e., cystic dysplastic kidney (CDK), our study indicates that the phenotype of the renal disease is common among these syndromes as well as abnormalities in other organs, suggesting the underlying similar molecular mechanisms.
Assuntos
Nefropatias/patologia , Síndrome Oculocerebrorrenal/patologia , Adolescente , Criança , Pré-Escolar , Evolução Fatal , Feminino , Transtornos do Crescimento/etiologia , Humanos , Rim/patologia , Nefropatias/etiologia , Falência Renal Crônica/etiologia , Masculino , Síndrome Oculocerebrorrenal/complicações , Transtornos Psicomotores/etiologiaRESUMO
Lowe syndrome is a genetic multi-system disorder affecting the central nervous system, lens and kidney. In this report, constricted palate, multiple eruption cysts and hematomas as the oral findings of a child diagnosed with Lowe syndrome is presented.
Assuntos
Síndrome Oculocerebrorrenal/complicações , Anormalidades Dentárias/etiologia , Cisto Dentígero/etiologia , Humanos , Lactente , Masculino , Síndrome Oculocerebrorrenal/patologia , Palato/anormalidades , Anormalidades Dentárias/patologiaRESUMO
This paper presents the dental findings of a child with the oculocerebrorenal syndrome of Lowe. The genetic abnormality in this condition results in an inborn error of inositol phosphate metabolism. Renal tubular dysfunction leads to metabolic acidosis and phosphaturia. At 4 years, generalised mobility of all primary teeth was noted. It is postulated that a defective inositol phosphate metabolism was responsible for the periodontal pathology found in this case. This is in direct contrast with previous reports of prolonged retention of primary teeth in children with this condition. Histology of extracted primary incisors demonstrated enlarged pulp chambers and mildly dysplastic dentin formation. This is consistent with a chronic subrachitic state, a known feature of Lowe syndrome, but no prominent interglobular dentin was present.
Assuntos
Síndrome Oculocerebrorrenal/diagnóstico , Doenças Dentárias/diagnóstico , Pré-Escolar , Cálculos Dentários/diagnóstico , Cálculos Dentários/etiologia , Cálculos Dentários/patologia , Diagnóstico Diferencial , Humanos , Incisivo/patologia , Masculino , Síndrome Oculocerebrorrenal/complicações , Síndrome Oculocerebrorrenal/patologia , Doenças Dentárias/etiologia , Doenças Dentárias/patologia , Mobilidade Dentária/diagnóstico , Mobilidade Dentária/etiologia , Mobilidade Dentária/patologiaRESUMO
The oculocerebrorenal syndrome of Lowe (OCRL), an X-linked disorder involving several organ systems, including the eyes, nervous system, and kidneys, is often difficult to diagnose because few pathologic data of diagnostic features about OCRL are available, and its rarity has hampered comprehensive investigations into its clinical spectrum. Recently, the genetic and biochemical abnormalities responsible for this syndrome have been reported. We have synthesized a cDNA probe of the OCRL locus using a polymerase chain reaction, in which there is no homology of cDNA sequence with human inositol polyphosphate-5-phosphatase (HUMINP5P); we have taken a genetic approach to diagnose this disorder in a 10-year-old male by using Northern blotting and have demonstrated the expression of mRNA in human tissues of a 17-week fetus by in situ hybridization. This paper presents a new method that should be an easy and helpful tool for diagnosing OCRL and that contributes a new aspect of this syndrome through in situ hybridization histochemical staining of normal fetal tissues.