Disease relevance of ZWS1

• The peroxisome biogenesis disorders (PBDs), including Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), are autosomal recessive diseases caused by deficiency of peroxisome assembly as well as malfunction of peroxisomes, where >10 genotypes have been reported [1].
• The mutant pups exhibited many of the clinical features of Zellweger syndrome patients, including intrauterine growth retardation, severe hypotonia, failure to feed, and neonatal death [2].
• Zellweger syndrome, the most severe phenotype, is characterized by hypotonia, psychomotor retardation and neuronal migration disorder [3].
• They were 27 patients with Zellweger syndrome (ZS), including two sib cases, three with neonatal adrenoleukodystrophy (NALD) and one with rhizomelic type chondrodysplasia punctata (RCDP) [4].
• Genetic relation between the Zellweger syndrome, infantile Refsum's disease, and rhizomelic chondrodysplasia punctata [5].

Psychiatry related information on ZWS1

• 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 [6].

High impact information on ZWS1

• These lethal diseases include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD) and infantile Refsum's disease (IRD), three phenotypes now thought to represent a continuum of clinical features that are most severe in ZS, milder in NALD and least severe in IRD2 [7].
• To investigate its possible involvement in Zellweger syndrome (ZS), an inborn error of peroxisome assembly, we cloned and sequenced cDNAs for human PMP70 and mapped the gene to chromosome 1 [8].
• Our results suggest that PMP70 plays an important role in peroxisome biogenesis and that mutations in PMP70 may be responsible for a subset of ZS patients [8].
• This observation extends the evidence that the Zellweger syndrome belongs to the newly formulated category of peroxisomal disorders [9].
• Other enzymes of the acyl DHAP pathway exhibited alterations in fibroblasts from patients with Zellweger syndrome, and the activity of the glycerophosphate acyltransferase was also reduced [10].

Chemical compound and disease context of ZWS1

• Deficiency of enzymes catalyzing the biosynthesis of glycerol-ether lipids in Zellweger syndrome. A new category of metabolic disease involving the absence of peroxisomes [10].
• Homogenates of fibroblasts from patients with a deficiency in peroxisomes (Zellweger syndrome and infantile Refsum's disease) showed a normal ability to beta-oxidize stearic acid, but the oxidation of pristanic and tetramethylheptadecanoic acid was decreased [11].
• L-Pipecolic acid, a cyclic imino acid produced during the degradation of lysine, accumulates in body fluids of infants with the generalized peroxisomal disorders, including Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease [12].
• We therefore treated two infants with the Zellweger syndrome with clofibrate (30 and 45 mg/kg body weight, respectively) for 3-4 wk [13].
• Absence of complementation was demonstrated between Zellweger syndrome and infantile Refsum's disease lines after polyethylene glycol fusion, with decreases of average activity of 11% relative to unfused cell mixtures [14].

Biological context of ZWS1

• In a structured follow-up cohort of 25 patients with PBD, not including ZS, three patients had an unusual pattern of cerebral white matter disease with onset past the age of 1, not conforming to any of the classic PBD phenotypes [15].
• A CG-I ZS patient (PBDE-04) possessed compound heterozygous, inactivating mutations: a missense point mutation resulting in Leu-664 --> Pro and a deletion of the sequence from Gly-634 to His-690 presumably caused by missplicing (splice site mutation) [16].
• The case of a newborn girl with Zellweger syndrome and a pericentric inversion of chromosome 7, 46,XX, inv(7)(p12q11.23), is reported [17].
• Peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome (ZS), are autosomal recessive diseases caused by a deficiency in peroxisome assembly as well as by a malfunction of peroxisomes, among which>10 genotypes have been identified [18].
• A patient with an atypical Zellweger syndrome had a missense mutation that was shown to disrupt the cell's ability to form peroxisomes [19].

Anatomical context of ZWS1

• HsPEX1 expression restored peroxisomal protein import in fibroblasts from three patients with ZS and NALD of complementation group I (CG-I), which is the highest-incidence PBD [16].
• Human PEX1 cloned by functional complementation on a CHO cell mutant is responsible for peroxisome-deficient Zellweger syndrome of complementation group I [16].
• When cells were cultured at 30 degrees C, catalase import was restored in the cell lines from patients with the NALD and IRD phenotypes, but to a much lesser extent in those with the ZS phenotype, indicating that temperature sensitivity varied inversely with the severity of the clinical phenotype [20].
• We measured the activity of dihydroxyacetone phosphate (DHAP) acyltransferase, a peroxisomal enzyme with a major role in ether lipid synthesis, in fibroblasts and leukocytes from patients with Zellweger syndrome [10].
• The Zellweger syndrome is a lethal hereditary disease characterized by the absence of peroxisomes (microbodies) in liver and kidney, and variable abnormalities in mitochondria [21].

Associations of ZWS1 with chemical compounds

• The PEX Gene Screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum [22].
• In bile of a patient with a peroxisome biogenesis disorder (Zellweger syndrome, ZS) LTE(4) was found to be slightly increased, whereas both omega-oxidation metabolites of LTE4, omega-hydroxy-LTE4 and omega-carboxy-LTE4, were highly increased (about 12-18 times) [23].
• These results support prior studies emphasizing the role of peroxisomes and the acyl DHAP pathway in cellular ether lipid synthesis, establish Zellweger syndrome cells as valuable for elucidating peroxisomal functions, and provide prenatal and postnatal diagnostic assays as well as potential therapeutic strategies for Zellweger syndrome [10].
• The conversion of intravenously administered [3H]THCA into cholic acid in another infant with Zellweger syndrome was only 7% [24].
• Metabolism of prostaglandin F2 alpha in Zellweger syndrome. Peroxisomal beta-oxidation is a major importance for in vivo degradation of prostaglandins in humans [25].

Regulatory relationships of ZWS1

• Dihydroxyacetone phosphate acyltransferase has similar Km (DHAP) values in both control and Zellweger syndrome cells; however, the value for the Vmax in Zellweger syndrome cells is only 6% of that found in the controls [26].
• The localization of the activity of the peroxisomal enzymes D-amino acid oxidase and hydroxyacid oxidase was studied at the light-microscopical level in livers and kidneys of control subjects and patients with Zellweger syndrome, an inherited disease characterized by a lack of intact peroxisomes [27].
• The biogenesis, assembly and import of the peroxisomal enzyme catalase was studied in human skin fibroblasts from control persons and from patients with the Zellweger syndrome [28].
• We have used this assay procedure to detect L-pipecolate oxidase in skin fibroblasts obtained from a control subject and from patients of hyperpipecolic acidaemia and Zellweger syndrome and found that this enzyme activity is present in the control, but absent or decreased in the patients with the peroxisomal disorders [29].

Other interactions of ZWS1

• Peroxisome biogenesis disorders (PBDs), such as Zellweger syndrome and neonatal adrenoleukodystrophy, are fatal genetic diseases that are autosomal recessive [30].
• Mutation in PEX16 is causal in the peroxisome-deficient Zellweger syndrome of complementation group D [18].
• PEX3 is the causal gene responsible for peroxisome membrane assembly-defective Zellweger syndrome of complementation group G [31].
• To clarify the novel pathogenic gene of PBD, we cloned the full-length human PAF-2 cDNA that morphologically and biochemically restores peroxisomes of group C Zellweger fibroblasts (the same as group 4 in the Kennedy-Krieger Institute) and identified two pathogenic mutations in the PAF-2 gene in two patients with group C Zellweger syndrome [32].
• We studied the PEX26 genotype in fibroblasts of eight CG8 patients--four with the ZS phenotype, two with NALD, and two with IRD [20].

Analytical, diagnostic and therapeutic context of ZWS1

• Similar findings in cultured amniocytes from 3 of 14 women in whom the fetus was at risk of the Zellweger syndrome permitted prenatal diagnosis [9].
• The study of very-long-chain fatty acids provides a convenient method for the early diagnosis and prenatal detection of the Zellweger syndrome [9].
• The profiles were compared with those of six patients with undetectable peroxisomes (Zellweger syndrome) and two siblings (N.B. and I.B.) whose defect of peroxisomal beta-oxidation could not be localized by morphological studies of peroxisomes or by immunoblotting of peroxisomal beta-oxidation proteins [33].
• 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) [34].
• Distinct immunofluorescence patterns were observed in cell lines from patients with Zellweger syndrome (a peroxisomal biogenesis disorder) belonging to different complementation groups [35].

References