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Biochimica Et Biophysica Acta Dec 2006Chemical and physico-chemical properties as well as physiological functions of major mammalian ether-linked glycerolipids, including plasmalogens were reviewed. Their... (Review)
Review
Chemical and physico-chemical properties as well as physiological functions of major mammalian ether-linked glycerolipids, including plasmalogens were reviewed. Their chemical structures were described and their effect on membrane fluidity and membrane fusion discussed. The recent generation of mouse models with ether lipid deficiency offered the possibility to study ether lipid and particularly plasmalogen functions in vivo. Ether lipid-deficient mice revealed severe phenotypic alterations, including arrest of spermatogenesis, development of cataract and defects in central nervous system myelination. In several cell culture systems lack of plasmalogens impaired intracellular cholesterol distribution affecting plasma membrane functions and structural changes of ER and Golgi cisternae. Based on these phenotypic anomalies that were accurately described conclusions were drawn on putative functions of plasmalogens. These functions were related to cell-cell or cell-extracellular matrix interactions, formation of lipid raft microdomains and intracellular cholesterol homeostasis. There are several human disorders, such as Zellweger syndrome, rhizomelic chondrodysplasia punctata, Alzheimer's disease, Down syndrome, and Niemann-Pick type C disease that are distinguished by altered tissue plasmalogen concentrations. The role plasmalogens might play in the pathology of these disorders is discussed.
Topics: Acyltransferases; Animals; Cataract; Cell Membrane; Cholesterol; Endoplasmic Reticulum; Golgi Apparatus; Hereditary Central Nervous System Demyelinating Diseases; Lens, Crystalline; Male; Membrane Fluidity; Membrane Fusion; Mice; Mice, Knockout; Peroxisomal Targeting Signal 2 Receptor; Plasmalogens; Receptors, Cytoplasmic and Nuclear; Spermatogenesis
PubMed: 17027098
DOI: 10.1016/j.bbamcr.2006.08.038 -
Frontiers in Pediatrics 2022Zellweger syndrome (ZS) is a congenital autosomal recessive disease within the spectrum of peroxisome biogenesis disorders, characterized by the impairment of peroxisome...
BACKGROUND
Zellweger syndrome (ZS) is a congenital autosomal recessive disease within the spectrum of peroxisome biogenesis disorders, characterized by the impairment of peroxisome assembly. The presence of peroxisome enzyme deficiencies leads to complex developmental sequelae, progressive disabilities, and multiorgan damage, due to intracellular accumulation of very-long-chain fatty acids (VLCFAs).
CASE PRESENTATION
We report the case of an infant affected by ZS in which agammaglobulinemia, detected through neonatal screening of congenital immunodeficiencies, appeared as a peculiar trait standing out among all the other classical characteristics of the syndrome. The exome analysis through next-generation sequencing (NGS), which had previously confirmed the diagnostic suspicion of ZS, was repeated, but no mutations causative of inborn error of immunity (humoral defect) were detected.
CONCLUSION
In this case, no genetic variants accountable for the abovementioned agammaglobulinemia were detected. Given that the scientific literature reports the involvement of peroxisomes in the activation of Nuclear Factor κ-light-chain-enhancer of activated B cells (NF-κB) pathway, which is crucial for B-cell survival, with this work, we hypothesize the existence of a link between ZS and humoral immunodeficiencies. Further studies are required to confirm this hypothesis.
PubMed: 35402347
DOI: 10.3389/fped.2022.852943 -
Orphanet Journal of Rare Diseases Jul 2022Pathogenic variants in PEX-genes can affect peroxisome assembly and function and cause Zellweger spectrum disorders (ZSDs), characterized by variable phenotypes in terms...
BACKGROUND
Pathogenic variants in PEX-genes can affect peroxisome assembly and function and cause Zellweger spectrum disorders (ZSDs), characterized by variable phenotypes in terms of disease severity, age of onset and clinical presentations. So far, defects in at least 15 PEX-genes have been implicated in Mendelian diseases, but in some of the ultra-rare ZSD subtypes genotype-phenotype correlations and disease mechanisms remain elusive.
METHODS
We report five families carrying biallelic variants in PEX13. The identified variants were initially evaluated by using a combination of computational approaches. Immunofluorescence and complementation studies on patient-derived fibroblasts were performed in two patients to investigate the cellular impact of the identified mutations.
RESULTS
Three out of five families carried a recurrent p.Arg294Trp non-synonymous variant. Individuals affected with PEX13-related ZSD presented heterogeneous clinical features, including hypotonia, developmental regression, hearing/vision impairment, progressive spasticity and brain leukodystrophy. Computational predictions highlighted the involvement of the Arg294 residue in PEX13 homodimerization, and the analysis of blind docking predicted that the p.Arg294Trp variant alters the formation of dimers, impairing the stability of the PEX13/PEX14 translocation module. Studies on muscle tissues and patient-derived fibroblasts revealed biochemical alterations of mitochondrial function and identified mislocalized mitochondria and a reduced number of peroxisomes with abnormal PEX13 concentration.
CONCLUSIONS
This study expands the phenotypic and mutational spectrum of PEX13-related ZSDs and also highlight a variety of disease mechanisms contributing to PEX13-related clinical phenotypes, including the emerging contribution of secondary mitochondrial dysfunction to the pathophysiology of ZSDs.
Topics: Genetic Association Studies; Humans; Membrane Proteins; Mutation; Peroxisomes; Zellweger Syndrome
PubMed: 35854306
DOI: 10.1186/s13023-022-02415-5 -
Biochimica Et Biophysica Acta Sep 2012Human peroxisome biogenesis disorders (PBDs) are a heterogeneous group of autosomal recessive disorders comprised of two clinically distinct subtypes: the Zellweger... (Review)
Review
Human peroxisome biogenesis disorders (PBDs) are a heterogeneous group of autosomal recessive disorders comprised of two clinically distinct subtypes: the Zellweger syndrome spectrum (ZSS) disorders and rhizomelic chondrodysplasia punctata (RCDP) type 1. PBDs are caused by defects in any of at least 14 different PEX genes, which encode proteins involved in peroxisome assembly and proliferation. Thirteen of these genes are associated with ZSS disorders. The genetic heterogeneity among PBDs and the inability to predict from the biochemical and clinical phenotype of a patient with ZSS which of the currently known 13 PEX genes is defective, has fostered the development of different strategies to identify the causative gene defects. These include PEX cDNA transfection complementation assays followed by sequencing of the thus identified PEX genes, and a PEX gene screen in which the most frequently mutated exons of the different PEX genes are analyzed. The benefits of DNA testing for PBDs include carrier testing of relatives, early prenatal testing or preimplantation genetic diagnosis in families with a recurrence risk for ZSS disorders, and insight in genotype-phenotype correlations, which may eventually assist to improve patient management. In this review we describe the current status of genetic analysis and the molecular basis of PBDs.
Topics: ATPases Associated with Diverse Cellular Activities; Adenosine Triphosphatases; Female; Genetic Association Studies; Humans; Membrane Proteins; Molecular Diagnostic Techniques; Mutation; Peroxisomal Disorders; Peroxisomes; Pregnancy; Prenatal Diagnosis; Protein Transport
PubMed: 22871920
DOI: 10.1016/j.bbadis.2012.04.006 -
Nature Clinical Practice.... Aug 2008Inborn errors of bile acid synthesis are rare genetic disorders that can present as neonatal cholestasis, neurologic disease or fat-soluble-vitamin deficiencies. There... (Review)
Review
Inborn errors of bile acid synthesis are rare genetic disorders that can present as neonatal cholestasis, neurologic disease or fat-soluble-vitamin deficiencies. There are nine known defects of bile acid synthesis, including oxysterol 7alpha-hydroxylase deficiency, Delta(4)-3-oxosteroid-5beta-reductase deficiency, 3beta-hydroxy-Delta(5)-C(27)-steroid dehydrogenase deficiency, cerebrotendinous xanthomatosis (also known as sterol 27-hydroxylase deficiency), alpha-methylacyl-CoA racemase deficiency, and Zellweger syndrome (also known as cerebrohepatorenal syndrome). These diseases are characterized by a failure to produce normal bile acids and an accumulation of unusual bile acids and bile acid intermediaries. Individuals with inborn errors of bile acid synthesis generally present with the hallmark features of normal or low serum bile acid concentrations, normal gamma-glutamyl transpeptidase concentrations and the absence of pruritus. Failure to diagnose any of these conditions can result in liver failure or progressive chronic liver disease. If recognized early, many patients can have a remarkable clinical response to oral bile acid therapy.
Topics: Bile Acids and Salts; Humans; Liver Diseases; Metabolism, Inborn Errors; Pruritus; gamma-Glutamyltransferase
PubMed: 18577977
DOI: 10.1038/ncpgasthep1179 -
Scientific Reports May 2018Peroxisomes are ubiquitous cell organelles involved in many metabolic and signaling functions. Their assembly requires peroxins, encoded by PEX genes. Mutations in PEX...
Peroxisomes are ubiquitous cell organelles involved in many metabolic and signaling functions. Their assembly requires peroxins, encoded by PEX genes. Mutations in PEX genes are the cause of Zellweger Syndrome spectrum (ZSS), a heterogeneous group of peroxisomal biogenesis disorders (PBD). The size and morphological features of peroxisomes are below the diffraction limit of light, which makes them attractive for super-resolution imaging. We applied Stimulated Emission Depletion (STED) microscopy to study the morphology of human peroxisomes and peroxisomal protein localization in human controls and ZSS patients. We defined the peroxisome morphology in healthy skin fibroblasts and the sub-diffraction phenotype of residual peroxisomal structures ('ghosts') in ZSS patients that revealed a relation between mutation severity and clinical phenotype. Further, we investigated the 70 kDa peroxisomal membrane protein (PMP70) abundance in relationship to the ZSS sub-diffraction phenotype. This work improves the morphological definition of peroxisomes. It expands current knowledge about peroxisome biogenesis and ZSS pathoethiology to the sub-diffraction phenotype including key peroxins and the characteristics of ghost peroxisomes.
Topics: ATP-Binding Cassette Transporters; Fibroblasts; Humans; PHEX Phosphate Regulating Neutral Endopeptidase; Peroxisomes; Zellweger Syndrome
PubMed: 29773809
DOI: 10.1038/s41598-018-24119-2 -
Translational Pediatrics Jul 2021Zellweger syndrome (ZS) is commonly manifested as facial deformities, hypotonia, and liver dysfunction. However, ZS caused by gene mutation shows a broad and dispersed...
BACKGROUND
Zellweger syndrome (ZS) is commonly manifested as facial deformities, hypotonia, and liver dysfunction. However, ZS caused by gene mutation shows a broad and dispersed clinical pattern. In this study, the gene in ZS was analyzed to enrich its clinical characteristics. Meanwhile, phenotypic and genotypic characteristics of Zellweger spectrum disorder (ZSD) induced by mutation were evaluated.
METHODS
The clinical data of newborn with ZS in our hospital were analyzed retrospectively. We performed WES and found that the infant carried the gene variant. We searched the biomedical literature databases (PubMed, Web of Science, and EMBASE) to compare clinical features and genotypes.
RESULTS
The neonate developed facial deformities, hypotonia, feeding difficulties, and seizures. Her homozygous variant was found in the gene (NM_017929: exon2: c.34del) inherited from both parents. Electronic databases, including our case, reported 32 pathogenic variants in . We found that variation c.292C> T accounted for the largest proportion of mutations (16/66, 24.24%). The proportion of deleterious mutations in ZS patients was significantly higher than that in NALD and IRD patients.
CONCLUSIONS
We identified pathogenic variations in the gene and expanded the known mutant spectrum. By comparing patients with mutations, the study determined that a significantly higher percentage of deleterious mutations in ZS was associated with severe clinical phenotypic characteristics.
PubMed: 34430430
DOI: 10.21037/tp-21-103 -
EMBO Reports Jan 2017PEX13 is an integral membrane protein on the peroxisome that regulates peroxisomal matrix protein import during peroxisome biogenesis. Mutations in PEX13 and other...
PEX13 is an integral membrane protein on the peroxisome that regulates peroxisomal matrix protein import during peroxisome biogenesis. Mutations in PEX13 and other peroxin proteins are associated with Zellweger syndrome spectrum (ZSS) disorders, a subtype of peroxisome biogenesis disorder characterized by prominent neurological, hepatic, and renal abnormalities leading to neonatal death. The lack of functional peroxisomes in ZSS patients is widely accepted as the underlying cause of disease; however, our understanding of disease pathogenesis is still incomplete. Here, we demonstrate that PEX13 is required for selective autophagy of Sindbis virus (virophagy) and of damaged mitochondria (mitophagy) and that disease-associated PEX13 mutants I326T and W313G are defective in mitophagy. The mitophagy function of PEX13 is shared with another peroxin family member PEX3, but not with two other peroxins, PEX14 and PEX19, which are required for general autophagy. Together, our results demonstrate that PEX13 is required for selective autophagy, and suggest that dysregulation of PEX13-mediated mitophagy may contribute to ZSS pathogenesis.
Topics: Animals; Autophagy; Cell Line; Gene Knockdown Techniques; Humans; Membrane Proteins; Mice; Mice, Transgenic; Mitochondria; Mitophagy; Peroxisomes; Protein Binding; Protein Transport; RNA, Small Interfering; Sindbis Virus; Ubiquitin-Protein Ligases; Zellweger Syndrome
PubMed: 27827795
DOI: 10.15252/embr.201642443 -
Annals of Medicine Jun 1992The peroxisomal diseases, which are rare inborn metabolic errors, often have serious effects on the well being of the individual and many of them are fatal at an early... (Review)
Review
The peroxisomal diseases, which are rare inborn metabolic errors, often have serious effects on the well being of the individual and many of them are fatal at an early age. The Zellweger cerebro-hepato-renal syndrome represents a group consisting of diseases with a generalized loss of peroxisomal functions and is considered as a prototype for peroxisomal dysfunction. The largest group includes those diseases where only a single peroxisomal function is impaired. The most common peroxisomal disease, x-linked adrenoleukodystrophy (ADL), belongs to this group, and neurological symptoms dominate among the patients. The primary diagnosis is usually based on clinical findings and measurement of accumulated or depleted metabolites in the body (e.g. very long chain fatty acids, bile acid intermediates or plasmalogens). Some progress has been made in treating of the peroxisomal diseases. Many patients with x-linked ALD have benefitted from the supplementation of the diet with long chain monounsaturated fatty acids like erucic acid or oleic acid with the simultaneous restriction of very long chain fatty acids. Docosahexenoate (C22:1) has also shown promising results in some studies.
Topics: Humans; Metabolism, Inborn Errors; Microbodies
PubMed: 1627308
DOI: 10.3109/07853899209147814 -
The European Respiratory Journal Oct 2020Major epidemics, including some that qualify as pandemics, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), HIV, influenza A... (Review)
Review
Epidemic and pandemic viral infections: impact on tuberculosis and the lung: A consensus by the World Association for Infectious Diseases and Immunological Disorders (WAidid), Global Tuberculosis Network (GTN), and members of the European Society of Clinical Microbiology and Infectious Diseases...
Major epidemics, including some that qualify as pandemics, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), HIV, influenza A (H1N1)pdm/09 and most recently COVID-19, affect the lung. Tuberculosis (TB) remains the top infectious disease killer, but apart from syndemic TB/HIV little is known regarding the interaction of viral epidemics and pandemics with TB. The aim of this consensus-based document is to describe the effects of viral infections resulting in epidemics and pandemics that affect the lung (MERS, SARS, HIV, influenza A (H1N1)pdm/09 and COVID-19) and their interactions with TB. A search of the scientific literature was performed. A writing committee of international experts including the European Centre for Disease Prevention and Control Public Health Emergency (ECDC PHE) team, the World Association for Infectious Diseases and Immunological Disorders (WAidid), the Global Tuberculosis Network (GTN), and members of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Mycobacterial Infections (ESGMYC) was established. Consensus was achieved after multiple rounds of revisions between the writing committee and a larger expert group. A Delphi process involving the core group of authors (excluding the ECDC PHE team) identified the areas requiring review/consensus, followed by a second round to refine the definitive consensus elements. The epidemiology and immunology of these viral infections and their interactions with TB are discussed with implications for diagnosis, treatment and prevention of airborne infections (infection control, viral containment and workplace safety). This consensus document represents a rapid and comprehensive summary on what is known on the topic.
Topics: BCG Vaccine; Betacoronavirus; COVID-19; Coronavirus Infections; Epidemics; HIV Infections; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Lung; Middle East Respiratory Syndrome Coronavirus; Pandemics; Pneumonia, Viral; Public Health; Respiratory Tract Infections; SARS-CoV-2; Severe Acute Respiratory Syndrome; Tuberculosis; Virus Diseases
PubMed: 32586885
DOI: 10.1183/13993003.01727-2020