Zellweger Syndrome

14,000,000 Leading Edge Experts on the ideXlab platform

Scan Science and Technology

Contact Leading Edge Experts & Companies

Scan Science and Technology

Contact Leading Edge Experts & Companies

The Experts below are selected from a list of 1272 Experts worldwide ranked by ideXlab platform

Virginia A Huszagh - One of the best experts on this subject based on the ideXlab platform.

  • Zellweger Syndrome knockout mouse models challenge putative peroxisomal β oxidation involvement in docosahexaenoic acid 22 6n 3 biosynthesis
    Molecular Genetics and Metabolism, 2001
    Co-Authors: Juan P Infante, Virginia A Huszagh
    Abstract:

    Abstract The putative involvement of peroxisomal β-oxidation in the biosynthetic pathway of docosahexaenoic acid (22:6n-3, DHA) synthesis is critically reviewed in light of experiments with two recently developed knockout mouse models for Zellweger Syndrome, a peroxisomal disorder affecting brain development. These mice were generated by targeted disruption of the PEX2 and PEX5 peroxisomal assembly genes encoding targeting signal receptor peroxins for the recognition and transport of a set of peroxisomal enzymes, including those of peroxisomal β-oxidation, to the peroxisomal matrix. Analysis of esterified 22:6n-3 concentrations in PEX2−/− and PEX5−/− mice do not support the hypothesized requirement of peroxisomal β-oxidation in 22:6n-3 synthesis, as only brain, but not liver or plasma, 22:6n-3 levels were decreased. Supplementation of PEX5+/− dams with 22:6n-3, although restoring the levels of brain 22:6n-3 in total lipids to that of controls, did not normalize the phenotype. These decreased brain 22:6n-3 concentrations appear to be secondary to impaired plasmalogen (sn-1-alkyl-, alkenyl-2-acyl glycerophospholipids) synthesis, probably at the level of the dihydroxyacetonephosphate acyltransferase (DHAP-AT), a peroxisomal enzyme catalyzing the first step in the synthesis of 22:6n-3-rich plasmalogens. To diminish the confounding effects of impaired plasmalogen synthesis in the brains of these Zellweger Syndrome mouse models, kinetic experiments with labeled precursors, such as 18:3n-3 or 20:5n-3, in liver or isolated hepatocytes, which have negligible amounts of plasmalogens, are suggested to establish the rates of 22:6n-3 biosynthesis and precursor–product relationships. Similar experiments using brain of the acyl-CoA oxidase knockout mouse model are proposed to confirm the lack of peroxisomal β-oxidation involvement in 22:6n-3 synthesis, since this mutation would not impair plasmalogen synthesis.

  • on the molecular etiology of decreased arachidonic 20 4n 6 docosapentaenoic 22 5n 6 and docosahexaenoic 22 6n 3 acids in Zellweger Syndrome and other peroxisomal disorders
    Molecular and Cellular Biochemistry, 1997
    Co-Authors: Juan P Infante, Virginia A Huszagh
    Abstract:

    Alterations in the metabolism of arachidonic (20:4n-6), docosapentaenoic (22:5n-6), and docosahexaenoic (22:6n-3) acids and other polyunsaturated fatty acids in Zellweger Syndrome and other peroxisomal disorders are reviewed. Previous proposals that peroxisomes are necessary for the synthesis of 22:6n-3 and 22:5n-6 are critically examined. The data suggest that 22:6n-3 is biosynthesized in mitochondria via a channelled carnitine-dependent pathway involving an n-3-specific D-4 desaturase, while 20:4n-6, 20:5n-3 and 22:5n-6 are synthesized by both mitochondrial and microsomal systems; these pathways are postulated to be interregulated as compensatory-redundant systems. Present evidence suggests that 22:6n-3-containing phospholipids may be required for the biochemical events involved in successful neuronal migration and developmental morphogenesis, and as structural cofactors for the functional assembly and integration of a variety of membrane enzymes, receptors, and other proteins in peroxisomes and other subcellular organelles. A defect in the mitochondrial desaturation pathway is proposed to be a primary etiologic factor in the clinicopathology of Zellweger Syndrome and other related disorders. Several implications of this proposal are examined relating to effects of pharmacological agents which appear to inhibit steps in this pathway, such as some hypolipidemics (fibrates), neuroleptics (phenothiazines and phenytoin) and prenatal alcohol exposure.

Ruud B.h. Schutgens - One of the best experts on this subject based on the ideXlab platform.

  • profiles of very long chain fatty acids in plasma fibroblasts and blood cells in Zellweger Syndrome x linked adrenoleukodystrophy and rhizomelic chondrodysplasia punctata
    Clinical Chemistry, 1993
    Co-Authors: Ruud B.h. Schutgens, R. J. A. Wanders, I W Bouman, A A Nijenhuis, M E J Frumau
    Abstract:

    Profiles of saturated very-long-chain (> C22) fatty acids were studied in plasma, fibroblasts, erythrocytes, platelets, and leukocytes of patients affected by peroxisomal disorders such as Zellweger Syndrome, X-linked adrenoleukodystrophy (X-ALD), and classic rhizomelic chondrodysplasia punctata (RCDP) and in controls. In Zellweger patients, the concentration of hexacosanoic acid (C26:0) and the C26:0/C22:0 ratio are greatly increased in plasma and fibroblasts. However, the plasma concentration of docosanoic acid (C22:0) is greatly decreased. Also in platelets, leukocytes, and to a lesser extent erythrocytes, the C26:0 concentrations and both the C26:0/C22:0 and C24:0/C22:0 ratios are greatly increased. The C24:0/C22:0 ratio is significantly increased in plasma, platelets, and leukocytes, but not in erythrocytes. In X-ALD, the C26:0 concentration and the C26:0/C22:0 and C24:0/C22:0 ratios are significantly increased in plasma, fibroblasts, platelets, and leukocytes, but the erythrocytes show substantial overlap in the 5-90% ranges between controls and patients. In RCDP, slightly increased C26:0 and C26:0/C22:0 ratios are found in erythrocytes, platelets, and leukocytes, but not in plasma and fibroblasts. We conclude that plasma and fibroblasts are the specimens of choice for biochemical diagnosis of Zellweger Syndrome and X-ALD, respectively. The slight increase in C26:0 in blood cells of RCDP patients suggests a decreased flux of very-long-chain fatty acids through the peroxisomal beta-oxidation pathway in liver in this genetic disorder.

  • acyl coa oxidase peroxisomal thiolase and dihydroxyacetone phosphate acyltransferase aberrant subcellular localization in Zellweger Syndrome
    Journal of Inherited Metabolic Disease, 1991
    Co-Authors: C W T Van Roermund, Joseph M. Tager, Stanley Brul, Ruud B.h. Schutgens
    Abstract:

    We have studied the presence and subcellular localization of peroxisomal 3-oxoacylcoenzyme A thiolase, acylcoenzyme A oxidase and acyl-CoA: dihydroxyacetonephosphate acyltransferase (DHAPAT) in fibroblasts from control subjects and patients with an inherited deficiency of peroxisomes (Zellweger Syndrome), using immunofluorescence spectroscopy and density gradient centrifugation techniques. The results show that Zellweger cells contain unprocessed thiolase and unprocessed acyl-CoA oxidase which are associated with structures containing a peroxisomal integral membrane protein of 69 kDa and having a density much lower than that of normal peroxisomes. The residual DHAPAT activity present in Zellweger cells is also contained in these structures. We conclude that these structures represent defectively assembled peroxisomes which may still be capable of importing some peroxisomal proteins.

Juan P Infante - One of the best experts on this subject based on the ideXlab platform.

  • Zellweger Syndrome knockout mouse models challenge putative peroxisomal β oxidation involvement in docosahexaenoic acid 22 6n 3 biosynthesis
    Molecular Genetics and Metabolism, 2001
    Co-Authors: Juan P Infante, Virginia A Huszagh
    Abstract:

    Abstract The putative involvement of peroxisomal β-oxidation in the biosynthetic pathway of docosahexaenoic acid (22:6n-3, DHA) synthesis is critically reviewed in light of experiments with two recently developed knockout mouse models for Zellweger Syndrome, a peroxisomal disorder affecting brain development. These mice were generated by targeted disruption of the PEX2 and PEX5 peroxisomal assembly genes encoding targeting signal receptor peroxins for the recognition and transport of a set of peroxisomal enzymes, including those of peroxisomal β-oxidation, to the peroxisomal matrix. Analysis of esterified 22:6n-3 concentrations in PEX2−/− and PEX5−/− mice do not support the hypothesized requirement of peroxisomal β-oxidation in 22:6n-3 synthesis, as only brain, but not liver or plasma, 22:6n-3 levels were decreased. Supplementation of PEX5+/− dams with 22:6n-3, although restoring the levels of brain 22:6n-3 in total lipids to that of controls, did not normalize the phenotype. These decreased brain 22:6n-3 concentrations appear to be secondary to impaired plasmalogen (sn-1-alkyl-, alkenyl-2-acyl glycerophospholipids) synthesis, probably at the level of the dihydroxyacetonephosphate acyltransferase (DHAP-AT), a peroxisomal enzyme catalyzing the first step in the synthesis of 22:6n-3-rich plasmalogens. To diminish the confounding effects of impaired plasmalogen synthesis in the brains of these Zellweger Syndrome mouse models, kinetic experiments with labeled precursors, such as 18:3n-3 or 20:5n-3, in liver or isolated hepatocytes, which have negligible amounts of plasmalogens, are suggested to establish the rates of 22:6n-3 biosynthesis and precursor–product relationships. Similar experiments using brain of the acyl-CoA oxidase knockout mouse model are proposed to confirm the lack of peroxisomal β-oxidation involvement in 22:6n-3 synthesis, since this mutation would not impair plasmalogen synthesis.

  • on the molecular etiology of decreased arachidonic 20 4n 6 docosapentaenoic 22 5n 6 and docosahexaenoic 22 6n 3 acids in Zellweger Syndrome and other peroxisomal disorders
    Molecular and Cellular Biochemistry, 1997
    Co-Authors: Juan P Infante, Virginia A Huszagh
    Abstract:

    Alterations in the metabolism of arachidonic (20:4n-6), docosapentaenoic (22:5n-6), and docosahexaenoic (22:6n-3) acids and other polyunsaturated fatty acids in Zellweger Syndrome and other peroxisomal disorders are reviewed. Previous proposals that peroxisomes are necessary for the synthesis of 22:6n-3 and 22:5n-6 are critically examined. The data suggest that 22:6n-3 is biosynthesized in mitochondria via a channelled carnitine-dependent pathway involving an n-3-specific D-4 desaturase, while 20:4n-6, 20:5n-3 and 22:5n-6 are synthesized by both mitochondrial and microsomal systems; these pathways are postulated to be interregulated as compensatory-redundant systems. Present evidence suggests that 22:6n-3-containing phospholipids may be required for the biochemical events involved in successful neuronal migration and developmental morphogenesis, and as structural cofactors for the functional assembly and integration of a variety of membrane enzymes, receptors, and other proteins in peroxisomes and other subcellular organelles. A defect in the mitochondrial desaturation pathway is proposed to be a primary etiologic factor in the clinicopathology of Zellweger Syndrome and other related disorders. Several implications of this proposal are examined relating to effects of pharmacological agents which appear to inhibit steps in this pathway, such as some hypolipidemics (fibrates), neuroleptics (phenothiazines and phenytoin) and prenatal alcohol exposure.

Hans R. Waterham - One of the best experts on this subject based on the ideXlab platform.

  • Chemical chaperones improve peroxisomal biogenesis in fibroblasts of mild Zellweger Syndrome spectrum patients
    Tijdschrift Voor Kindergeneeskunde, 2013
    Co-Authors: Kevin Berendse, Ronald J A Wanders, Bwee Tien Poll-the, Merel S. Ebberink, Lodewijk Ijlst, Hans R. Waterham
    Abstract:

    s ingediend voor het Amsterdam Kindersymposium 2013 21 Chemical chaperones improve peroxisomal biogenesis in fibroblasts of mild Zellweger Syndrome spectrum patients Kevin Bere ndse (1,2), Merel S. Ebberink (1), Lodewijk IJlst (1), Bwee Tien Poll-The (2), Ronald J.A. Wanders(1), Hans R. Waterham (1) (1) Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, the Netherlands (2) Department of Paediatric Neurology, Emma Children’s Hospital, Academic Medical Center, Amsterdam, the Netherlands INTRODUCTION Zellweger Syndrome spectrum (ZSS) disorders are multisystem genetic disorders which lack functional peroxisomes due to a defect in one of the PEX genes. The ZSS include three phenotypes, which represent a spectrum of disease severity with Zellweger Syndrome (ZS) being the most severe. In contrast to patients with the ZS phenotype, mild patients can be characterized by very mildly abnormal peroxisomal parameters in cultured skin fi broblasts, including a mosaic catalase immunofl uorescence pattern. Such a mosaic pattern is described for specifi c missense mutations in various PEX genes. Possibly, these missense mutations cause an unstable and/or incorrect folded native state of the protein. We hypothesize that the functional activity of the mutant PEX1 can be enhanced by promoting protein folding with chemical chaperones (e.g. glycerol or arginine) and thereby stimulating peroxisome biogenesis. METHODS Fibroblasts from four patients with a defect in PEX1 and two controls were cultured for up to three weeks in DMEM medium with diff erent concentrations of arginine or glycerol. To determine the eff ect of diff erent chemicals on peroxisome biogenesis we studied the following parameters: (1) the levels of PEX1 protein, (2) the peroxisomal protein import capacity, (3) the levels of intra peroxisomal processed protein, and (4) the capacity to β-oxidize very long chain fatty acids. CONCLUSION The addition of arginine or glycerol to the medium improved both the peroxisomal biogenesis and the peroxisomal metabolic state of fi broblasts with a missense mutation in PEX1. We hypothesize that a signifi cant number of ZSS patients may benefi t from arginine treatment.

  • defective lipid remodeling of gpi anchors in peroxisomal disorders Zellweger Syndrome and rhizomelic chondrodysplasia punctata
    Journal of Lipid Research, 2012
    Co-Authors: Noriyuki Kanzawa, Nobuyuki Shimozawa, Hans R. Waterham, Kazutaka Ikeda, Yoshiko Murakami, Satoru Mukai, Morihisa Fujita, Yusuke Maeda, Ryo Taguchi
    Abstract:

    Many cell surface proteins in mammalian cells are anchored to the plasma membrane via glycosylphosphatidylinositol (GPI). The predominant form of mammalian GPI contains 1-alkyl-2-acyl phosphatidylinositol (PI), which is generated by lipid remodeling from diacyl PI. The conversion of diacyl PI to 1-alkyl-2-acyl PI occurs in the ER at the third intermediate in the GPI biosynthetic pathway. This lipid remodeling requires the alkyl-phospholipid biosynthetic pathway in peroxisome. Indeed, cells defective in dihydroxyacetone phosphate acyltransferase (DHAP-AT) or alkyl-DHAP synthase express only the diacyl form of GPI-anchored proteins. A defect in the alkyl-phospholipid biosynthetic pathway causes a peroxisomal disorder, rhizomelic chondrodysplasia punctata (RCDP), and defective biogenesis of peroxisomes causes Zellweger Syndrome, both of which are lethal genetic diseases with multiple clinical phenotypes such as psychomotor defects, mental retardation, and skeletal abnormalities. Here, we report that GPI lipid remodeling is defective in cells from patients with Zellweger Syndrome having mutations in the peroxisomal biogenesis factors PEX5, PEX16, and PEX19 and in cells from patients with RCDP types 1, 2, and 3 caused by mutations in PEX7, DHAP-AT, and alkyl-DHAP synthase, respectively. Absence of the 1-alkyl-2-acyl form of GPI-anchored proteins might account for some of the complex phenotypes of these two major peroxisomal disorders.

  • Genetic classification and mutational spectrum of more than 600 patients with a Zellweger Syndrome spectrum disorder
    Human Mutation, 2010
    Co-Authors: Merel Sanne Ebberink, Ronald J A Wanders, Petra Mooyer, Jeannette Gootjes, Janet Koster, Hans R. Waterham
    Abstract:

    The autosomal recessive Zellweger Syndrome spectrum (ZSS) disorders comprise a main subgroup of the peroxisome biogenesis disorders and can be caused by mutations in any of 12 different currently identified PEX genes resulting in severe multi-systemic disorders. To get insight into the spectrum of PEX gene defects among ZSS disorders and to investigate if additional human PEX genes are required for functional peroxisome biogenesis, we assigned over 600 ZSS fibroblast cell lines to different genetic complementation groups. These fibroblast cell lines were subjected to a complementation assay involving fusion by means of polyethylene glycol or a PEX cDNA transfection assay specifically developed for this purpose. In a majority of the cell lines we subsequently determined the underlying mutations by sequence analysis of the implicated PEX genes.The PEX cDNA transfection assay allows for the rapid identification of PEX genes defective in ZSS patients. The assignment of over 600 fibroblast cell lines to different genetic complementation groups provides the most comprehensive and representative overview of the frequency distribution of the different PEX gene defects. We did not identify any novel genetic complementation group, suggesting that all PEX gene defects resulting in peroxisome deficiency are currently known.

  • spectrum of pex6 mutations in Zellweger Syndrome spectrum patients
    Human Mutation, 2010
    Co-Authors: Merel S. Ebberink, Ronald J A Wanders, Janet Kofster, Hans R. Waterham
    Abstract:

    The autosomal recessive Zellweger Syndrome spectrum (ZSS) disorders comprise a main subgroup of the peroxisome biogenesis disorders. The ZSS disorders can be caused by mutations in any of 12 different currently identified PEX genes resulting in severe, often lethal, multi-systemic disorders. Defects in the PEX6 gene are the second most common cause for ZSS disorders. The encoded protein PEX6 belongs to the AAA ATPase family and contains two AAA cassettes and an AAA protein family signature. The PEX6 gene consists of 17 exons and previously mutations in the PEX6 gene were found to be scattered over all exons. We developed a post-PCR high-resolution melting (HRM) curve assay to scan the PEX6 gene for potential sequence variations followed by selective sequencing to identify these. We analyzed the PEX6 genes of 75 patients assigned to the PEX6 complementation group. We identified a total of 77 different mutations of which 47 mutations have not been reported previously, and 14 polymorphic variants. © 2009 Wiley-Liss, Inc.

Masao Iwamori - One of the best experts on this subject based on the ideXlab platform.

  • altered phospholipid molecular species and glycolipid composition in brain liver and fibroblasts of Zellweger Syndrome
    Neuroscience Letters, 2013
    Co-Authors: Celine Miyazaki, Makiko Saitoh, Masao Iwamori, Sachio Takashima, Masayuki Itoh, Ann B Moser, Sumimasa Yamashita, Makoto Miyagishi, Masashi Mizuguchi
    Abstract:

    We studied the altered molecular species of lipids in brain and liver tissues, and fibroblasts from patients with Zellweger Syndrome (ZS). ZS cerebellum samples contained a higher amount of sphingomyelin with shorter chain fatty acids compared to that in normal controls. The amount of phosphatidylethanolamine (PE) was less than half of that in controls, with the absence of the PE-type of plasmalogen. Gangliosides were accumulated in the brains and fibroblasts of ZS patients. To investigate whether or not impaired beta-oxidation of very long chain fatty acids and/or plasmalogen synthesis affects glycolipids metabolism, RNAi of peroxisomal acylCo-A oxidase (ACOX1) and glyceronephosphate O-acyltransferase (GNPAT) was performed using cultured neural cells. In neuronal F3-Ngn1 cells, ACOX1 and GNPAT silencing up-regulated ceramide galactosyltransferase (UGT8) mRNA expression, and down-regulated UDP-glucose ceramide glucosyltransferase (UGCG). These results suggest that both impaired beta-oxidation of very long chain fatty acids and plasmalogen synthesis affect glycolipid metabolism in neuronal cells.

  • phosphatidyl ethanolamine with increased polyunsaturated fatty acids in compensation for plasmalogen defect in the Zellweger Syndrome brain
    Neuroscience Letters, 2009
    Co-Authors: Makiko Saitoh, Masashi Mizuguchi, Sachio Takashima, Masayuki Itoh, Masao Iwamori
    Abstract:

    Abstract To elucidate the neuropathological mechanism of Zellweger Syndrome (ZS), we studied changes in the molecular species of glycerophospholipids in the cerebral tissue by thin-layer chromatography (TLC) and fast atom bombardment mass spectrometry (FABMS). First, we estimated the amount of plasmalogens by TLC. Plasmalogen-type phosphatidyl ethanolamine (PE) accounted for 30% of the total PE in the control brain, but was absent in the ZS brain. Plasmalogen-type phosphatidyl choline (PC) was undetectable in both control and ZS brains. Next, we analyzed plasmalogen-type PE by FABMS. Oleic (18:1), arachidonic (20:4) and docosapentanoic (22:5) acids were present in the control gray matter, but not in the ZS gray matter. In compensation for the defect of plasmalogen, the level of diacyl PE with polyunsaturated fatty acids, 20:4, 22:4, 22:5 and 22:6, was higher in the ZS brain than that in the control brain. These results indicate an alteration in the molecular species of PE, which may cause abnormal neural membrane fluidity and excessive vulnerability to oxygen stress.

  • increase of ceramide monohexoside and dipalmitoyl glycerophospholipids in the brain of Zellweger Syndrome
    Neuroscience Letters, 2007
    Co-Authors: Makiko Saitoh, Masashi Mizuguchi, Masao Iwamori, Sachio Takashima, Masayuki Itoh, Yoichi Sakakihara, Shigehiko Kamoshita, Takashi Igarashi
    Abstract:

    The lipid composition and molecular species of phospholipids were examined in the brain of a patient with Zellweger Syndrome (ZS), and were compared with those of control infants. In the cerebral gray matter of the ZS patient, the amounts of ceramide monohexoside and cholesterol ester were larger than those of controls. By contrast, the amount of ceramide monohexoside in the white matter was smaller in the ZS patient than that in the age-matched control. Although the amount of phosphatidylcholine (PC) plus phosphatidylserine (PS) was the same, dipalmitoyl PC and PS were increased in both the gray and white matter of the ZS cerebrum. These alterations in the molecular species of brain lipids may play crucial roles in the pathogenesis of ZS.