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Proceedings of the National Academy of... Nov 1991By both histological and biochemical criteria, peroxisomes in patients with Zellweger syndrome appear to be absent or severely deficient. By using 15-30% (wt/vol)... (Comparative Study)
Comparative Study
By both histological and biochemical criteria, peroxisomes in patients with Zellweger syndrome appear to be absent or severely deficient. By using 15-30% (wt/vol) Nycodenz/sucrose gradients to study the subcellular localization of extraperoxisomal catalase activity, a commonly used marker for mature peroxisomes, we detected a single peak of activity in Zellweger syndrome fibroblasts at an equilibrium density of 1.13 g/cm3, lower than the expected 1.17 g/cm3 of mature peroxisomes. Upon recentrifugation in either the original gradient or one with a higher salt concentration, essentially all catalase activity was recovered in fractions of the original densities. The activity of the catalase peak was further analyzed by a digitonin titration and filtration assay in combination with Triton X-100 treatment. The catalase activity passed through 0.1-microns and 0.22-microns but was retained on 0.025-microns membrane filters (mean pore size). After treatment with Triton X-100 nearly all catalase activity passed through the filters. The results from fractionations data, digitonin latency measurement, and the detergent effect on the filtration behavior suggest that catalase is not free in the cytosol of Zellweger syndrome fibroblasts as commonly thought but in particles (W-particles). Similar low-density catalase-containing particles, distinct from peroxisomes, are also found in normal fibroblasts. We found that L-alpha-hydroxyacid oxidase, another peroxisomal matrix enzyme, is also present in W-particles derived from normal and Zellweger syndrome fibroblasts. We speculate that the low-density catalase-containing W-particle may represent an immature or incomplete form of peroxisome distinct from previously described "peroxisomal ghosts" in Zellweger syndrome fibroblasts.
Topics: Biomarkers; Catalase; Cell Fractionation; Cell Line; Centrifugation, Density Gradient; Digitonin; Fibroblasts; Humans; Microbodies; Organelles; Zellweger Syndrome
PubMed: 1946426
DOI: 10.1073/pnas.88.22.10084 -
Molecular Genetics and Metabolism Nov 2021Peroxisome Biogenesis Disorders-Zellweger spectrum disorder (PBD-ZSD) is a rare, autosomal recessive peroxisome biogenesis disorder that presents with variable symptoms.... (Review)
Review
Peroxisome Biogenesis Disorders-Zellweger spectrum disorder (PBD-ZSD) is a rare, autosomal recessive peroxisome biogenesis disorder that presents with variable symptoms. In patients with PBD-ZSD, pathogenic variants in the PEX family of genes disrupt normal peroxisomal function, impairing α- and β-oxidation of very-long-chain fatty acids and synthesis of bile acids, resulting in increased levels of toxic bile acid intermediates and multisystem organ damage. The spectrum of severity in PBD-ZSD is variable, with some patients dying in the first year of life, while others live into adulthood. Symptoms of mild PBD-ZSD include various combinations of developmental delay, craniofacial dysmorphic features, visual impairment, sensorineural hearing loss, liver disease, and adrenal insufficiency. Disease progression in mild PBD-ZSD is generally slow, and may include extended periods of stability in some cases. The presence and extent to which symptoms occur in mild PBD-ZSD represents a diagnostic challenge that can cause delays in diagnosis with potential significant implications related to disease monitoring and treatment. There is some support for the pharmacologic therapies of Lorenzo's oil, docosohexanoic acid, and batyl alcohol in altering symptoms; however, systematic long-term studies are lacking. Cholic acid (CA) therapy has demonstrated treatment efficacy in patients with PBD-ZSD, including decreased toxic bile acid intermediates, transaminase levels, and liver inflammation, with improvement in growth parameters. However, these responses are most apparent in patients diagnosed and treated at a young age. Advanced liver disease may limit the efficacy of CA, underscoring the need to diagnose and treat these patients before significant liver damage and other related complications occur. Here we discuss the signs and symptoms of PBD-ZSD in patients with mild disease, standard diagnostic tools, factors affecting disease management, and available pharmacological interventions.
Topics: Adult; Clinical Trials as Topic; Disease Management; Humans; Longitudinal Studies; Phenotype; Zellweger Syndrome
PubMed: 34625341
DOI: 10.1016/j.ymgme.2021.09.007 -
Genetics in Medicine : Official Journal... Nov 2023Zellweger spectrum disorders (ZSDs) are known as autosomal recessive disorders caused by defective peroxisome biogenesis due to bi-allelic pathogenic variants in any of...
PURPOSE
Zellweger spectrum disorders (ZSDs) are known as autosomal recessive disorders caused by defective peroxisome biogenesis due to bi-allelic pathogenic variants in any of at least 13 different PEX genes. Here, we report 2 unrelated patients who present with an autosomal dominant ZSD.
METHODS
We performed biochemical and genetic studies in blood and skin fibroblasts of the patients and demonstrated the pathogenicity of the identified PEX14 variants by functional cell studies.
RESULTS
We identified 2 different single heterozygous de novo variants in the PEX14 genes of 2 patients diagnosed with ZSD. Both variants cause messenger RNA mis-splicing, leading to stable expression of similar C-terminally truncated PEX14 proteins. Functional studies indicated that the truncated PEX14 proteins lost their function in peroxisomal matrix protein import and cause increased degradation of peroxisomes, ie, pexophagy, thus exerting a dominant-negative effect on peroxisome functioning. Inhibition of pexophagy by different autophagy inhibitors or genetic knockdown of the peroxisomal autophagy receptor NBR1 resulted in restoration of peroxisomal functions in the patients' fibroblasts.
CONCLUSION
Our finding of an autosomal dominant ZSD expands the genetic repertoire of ZSDs. Our study underscores that single heterozygous variants should not be ignored as possible genetic cause of diseases with an established autosomal recessive mode of inheritance.
Topics: Humans; Alleles; Peroxisomes; Protein Transport; Proteins; Zellweger Syndrome
PubMed: 37493040
DOI: 10.1016/j.gim.2023.100944 -
Trends in Genetics : TIG Aug 2000Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease and rhizomelic chondrodysplasia punctata are progressive disorders characterized by loss of... (Review)
Review
Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease and rhizomelic chondrodysplasia punctata are progressive disorders characterized by loss of multiple peroxisomal metabolic functions. These diseases are inherited in an autosomal recessive manner, are caused by defects in the import of peroxisomal matrix proteins and are referred to as the peroxisome biogenesis disorders (PBDs). Recent studies have identified the PEX genes that are mutated in 11 of the 12 known complementation groups of PBD patients. This article reviews these advances in PBD genetics and discusses how studies of human PEX genes, their protein products and PBD cell lines are shaping current models of peroxisome biogenesis.
Topics: Humans; Models, Biological; Peroxisomal Disorders
PubMed: 10904262
DOI: 10.1016/s0168-9525(00)02056-4 -
Sudanese Journal of Paediatrics 2011Zellweger syndrome, a paradigm of human peroxisomal disorders is characterized by dysmorphic features, hypotonia, severe neuro-developmental delay, hepatomegaly, renal...
Zellweger syndrome, a paradigm of human peroxisomal disorders is characterized by dysmorphic features, hypotonia, severe neuro-developmental delay, hepatomegaly, renal cysts, sensorineural deafness and retinal dysfunction. This is a case report of a baby boy born with facial dysmorphism, profound hypotonia, seizures, and hepatomegaly. The diagnosis was not evident initially but only later when he presented with obstructive jaundiced and renal cysts. He died at the age of seven months. Biochemical studies revealed elevation of very long chain fatty acids and phytanic acid consistent with a peroxisomal disorder. The recognition of this syndrome is important since it is a fatal hereditary disease. Zellweger syndrome should be included in the differential diagnosis of infantile hypotonia and dysmorphism.
PubMed: 27493320
DOI: No ID Found -
Neurology India 2022
Topics: ATPases Associated with Diverse Cellular Activities; Humans; Neuroimaging; Phenotype; Zellweger Syndrome
PubMed: 35263876
DOI: 10.4103/0028-3886.338656 -
Archives of Pathology & Laboratory... Jan 2003
Topics: Adrenoleukodystrophy; Humans; Infant; Male; Zellweger Syndrome
PubMed: 12562281
DOI: 10.5858/2003-127-119- -
The EMBO Journal Jun 2020Primary cilia are antenna-like organelles on the surface of most mammalian cells that receive sonic hedgehog (Shh) signaling in embryogenesis and carcinogenesis....
Primary cilia are antenna-like organelles on the surface of most mammalian cells that receive sonic hedgehog (Shh) signaling in embryogenesis and carcinogenesis. Cellular cholesterol functions as a direct activator of a seven-transmembrane oncoprotein called Smoothened (Smo) and thereby induces Smo accumulation on the ciliary membrane where it transduces the Shh signal. However, how cholesterol is supplied to the ciliary membrane remains unclear. Here, we report that peroxisomes are essential for the transport of cholesterol into the ciliary membrane. Zellweger syndrome (ZS) is a peroxisome-deficient hereditary disorder with several ciliopathy-related features and cells from these patients showed a reduced cholesterol level in the ciliary membrane. Reverse genetics approaches revealed that the GTP exchange factor Rabin8, the Rab GTPase Rab10, and the microtubule minus-end-directed kinesin KIFC3 form a peroxisome-associated complex to control the movement of peroxisomes along microtubules, enabling communication between peroxisomes and ciliary pocket membranes. Our findings suggest that insufficient ciliary cholesterol levels may underlie ciliopathies.
Topics: Cells, Cultured; Cholesterol; Cilia; Germinal Center Kinases; Humans; Kinesins; Microtubules; Smoothened Receptor; Zellweger Syndrome; rab GTP-Binding Proteins
PubMed: 32368833
DOI: 10.15252/embj.2019103499 -
Molecular Genetics and Metabolism... Jun 2020
PubMed: 32373468
DOI: 10.1016/j.ymgmr.2020.100590 -
Cardiovascular Therapeutics Apr 2017Acute coronary syndrome is a life-threatening condition of utmost clinical importance, which, despite recent progress in the field, is still associated with high... (Review)
Review
Acute coronary syndrome is a life-threatening condition of utmost clinical importance, which, despite recent progress in the field, is still associated with high morbidity and mortality. Acute coronary syndrome results from a rupture or erosion of vulnerable atherosclerotic plaque with secondary platelet activation and thrombus formation, which leads to partial or complete luminal obstruction of a coronary artery. During the last decade, scientific evidence demonstrated that when an acute coronary event occurs, several nonculprit plaques are in a "vulnerable" state. Among the promising approaches, several investigations provided evidence of photodynamic therapy (PDT)-induced stabilization and regression of atherosclerotic plaque. Significant development of PDT strategies improved its therapeutic outcome. This review addresses PDT's pertinence and major problems/challenges toward its translation to a clinical reality.
Topics: Acute Coronary Syndrome; Animals; Coronary Artery Disease; Coronary Vessels; Humans; Photochemotherapy; Photosensitizing Agents; Plaque, Atherosclerotic; Rupture, Spontaneous; Theranostic Nanomedicine; Translational Research, Biomedical; Treatment Outcome
PubMed: 27893195
DOI: 10.1111/1755-5922.12238