Peroxisomal disorders: A newly recognised group of genetic diseases

Schutgens, R. B. H.; Heymans, H. S. A.; Wanders, Ronald J. A.; Bosch, H. van den; Tager, J. M.

doi:10.1007/bf00441734

Cited by 304 publications

(114 citation statements)

References 101 publications

(103 reference statements)

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“…The The absence of cytochemically demonstrable xanthine oxidase in the rosy-506 mutant establishes peroxisomes of Malpighian tubule as a site at which the structural mutation of the rosy-506 mutant is expressed. The apparent effects on catalase activity that we found were less expected, although they might have been anticipated from the experience with certain human disorders in which single gene mutations seem to have multiple effects on peroxisomes (2)(3)(4). Several possible explanations for the effects of the rosy mutation on catalase need exploring.…”

Section: Discussionmentioning

confidence: 54%

“…Deficits in one or more of the peroxisomal enzymes and possible defects in peroxisomal structure are correlated with certain human inherited metabolic diseases (1)(2)(3)(4). These diseases are still poorly understood, in part because different tissues show different effects of the mutation and in part because alterations in single genes can seemingly have multiple effects on the peroxisomes.…”

mentioning

confidence: 99%

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Peroxisomes in wild-type and rosy mutant Drosophila melanogaster.

Beard

Holtzman

1987

Proc. Natl. Acad. Sci. U.S.A.

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This study shows that peroxisomes are abundant in the Malpighian tubule and gut of wild-type Oregon R Drosophila melanogaster and that the peroxisomal population of the rosy-506 eye-color mutant differs from that of the wild type. Catalase activity in wild-type flies is demonstrable in bodies of appearance and centrifugal behavior comparable to the perixosomes of vertebrate tissues. Xanthine oxidase (xanthine:oxygen oxidoreductase, EC 1. Deficits in one or more of the peroxisomal enzymes and possible defects in peroxisomal structure are correlated with certain human inherited metabolic diseases (1-4). These diseases are still poorly understood, in part because different tissues show different effects of the mutation and in part because alterations in single genes can seemingly have multiple effects on the peroxisomes. Studies of the disorders are made difficult by their rareness and by the obvious limits of working with human material. It would be helpful to study analogues of the disorders in animals amenable to detailed analysis, but thus far such analogues have not been available. We chose to initiate our explorations for peroxisomal mutants in Drosophila by comparing wild-type Oregon R strain flies with the rosy-506 eye-color mutant, in which 90% of the structural gene for xanthine dehydrogenase (xanthine: NAD+ oxidoreductase, EC 1.1.1.204) is deleted (5, 6). This protein is a bifunctional oxidoreductase that can act as a dehydrogenase or as an oxidase (xanthine:oxygen oxidoreductase, EC 1.1.3.22) depending upon substrate and acceptor availability (7,8). The oxidase activity of the enzyme is critical to the degradation of purines in many organisms; the dehydrogenase function is central to the formation of pterinebased eye-color pigments in Drosophila. We suspected that this protein might be peroxisomal because (i) when acting as an oxidase, it produces hydrogen peroxide, a common feature of peroxisomal oxidases; (ii) it requires flavin in generating peroxide, as is found for many other peroxisomal oxidases; and (iii) its role in punine degradation is potentially functionally linked to activity of allantoicase and uricase, known peroxisomal enzymes (9). The subcellular localization of xanthine oxidase is not clearly established. Some cell fractionation studies show most of the enzyme to be soluble (9, 10), while other investigations report some xanthine oxidase cosedimenting with peroxisomal enzymes (11, 12).The study reported here identifies peroxisomes in the Malpighian tubule and gut of adult Drosophila wild-type Oregon R and rosy-506 strains, by virtue of their content of catalase, the peroxisomal "marker" enzyme. To localize xanthine oxidase, we have adapted cytochemical methods used to demonstrate other oxidases. With these methods, we have shown the presence of xanthine oxidase in peroxisomes of wild-type flies and the absence of this enzyme in rosy-506 flies. We also find signs that, as in the human mutations, a relatively simple genetic change can have complex effects on the peroxisomes. Prel...

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Section: Discussionmentioning

confidence: 54%

mentioning

confidence: 99%

Peroxisomes in wild-type and rosy mutant Drosophila melanogaster.

Beard

Holtzman

1987

Proc. Natl. Acad. Sci. U.S.A.

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“…It is to be noted here that peroxisomal disorders such as Zellweger syndrome, neonatal adrenoleukodysuophy, and infantile Refsum disease are frequently accompanied by retinitis pigmentosa (32). It has been also reported that at least some patients with Leber congenital amaurosis may have one of the "peroxisomal disorders," because a liver biopsy specimen lacked peroxisomes (17).…”

Section: Discussionmentioning

confidence: 87%

Localization of nonspecific lipid transfer protein (nsLTP = sterol carrier protein 2) and acyl-CoA oxidase in peroxisomes of pigment epithelial cells of rat retina.

Deguchi

Yamamoto²,

Fujiki³

et al. 1992

J Histochem Cytochem.

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We investigated the localization of nonspecific lipid transfer protein (nsLTP) in rat retina, especially in the pigment epithelial (WE) cells, by the avidin-biotin-peroxidase complex method on ayosections for light miaoscopy and by the ayoimmunogold method for electron microscopy. Light miaoscopic observation revealed that the W E , inner segment layer, nerve fiber layer, and Miiller ells contain nsLTP. In the RPE cells gold particles were exclusively concentrated in the small peroxisomes (miaoperoxisomes; 0.1-0.3 pm in diameter), which were identified by double staining using anti-nsLTP and anti-catalase antibodies. In the peroxisomes gold particles were distributed homogeneously in the matri-

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“…The peroxisome biogenesis disorders (PBDs) (MIM# 601539) are a group of autosomal recessive disorders that result from a failure to correctly import peroxisomal matrix or membrane proteins, and the subsequent disruption of multiple peroxisomal functions [Schutgens et al, 1986;van den Bosch et al, 1992;Moser, 1993;Lazarow and DOI: 10.1002/humu.9356 Gould et al, 2001]. The PBDs are caused by mutations in PEX genes, which encode a diverse range of protein products, called peroxins, required for the normal biogenesis of the peroxisome [Distel et al, 1996;Subramani et al, 2000;Gould and Valle, 2000;Purdue and Lazarow, 2001;Weller et al, 2003].…”

Section: Introductionmentioning

confidence: 99%

NovelPEX1 coding mutations and 5′ UTR regulatory polymorphisms

et al. 2005

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Zellweger syndrome and its milder variants-neonatal adrenoleukodystrophy and infantileRefsum disease-comprise a clinical continuum of diseases referred to as the Zellweger spectrum. Mutations in the PEX1 gene, which consists of 24 exons and encodes a AAA ATPase protein required for peroxisomal protein import, account for approximately twothirds of the known Zellweger spectrum patient mutations. In this paper, we report on four novel PEX1 mutations and two polymorphisms in an Australasian cohort. Two of the mutations-c.1108_1109insA and c.2391_2392delTC-that lead to the introduction of a premature termination codon in exons 5 and 14, respectively, are associated with the severe Zellweger phenotype. One patient with a milder disease phenotype was a compound heterozygote for two missense mutations (I989T and R998Q), both affecting amino acids in the second, C-terminal AAA domain of the protein. PTS1 protein import levels in cultured skin fibroblasts from this patient were almost 20% of normal control levels. We have also characterized two co-segregating polymorphisms in the 5' UTR of the PEX1 gene. Based on reporter assays, the c.-137T>C polymorphism leads to reduced PEX1 expression, whereas the c.-53C>G polymorphism leads to increased expression. When present together, these regulatory polymorphisms lead to near-normal PEX1 expression. Altered PEX1 expression due to the presence of either the c.-137T>C or the c.-53C>G variant could impact on residual PEX1 function if another co-allelic mutation was present which did not completely abolish PEX1 function. It also follows that the presence of polymorphisms in the PEX1 promoter region could have implications for patients with mutations in other PEX proteins known to interact with PEX1, such as PEX6. Thus, although not deleterious in control individuals, these polymorphisms could contribute to phenotypic heterogeneity among Zellweger spectrum patients

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Peroxisomal disorders: A newly recognised group of genetic diseases

Cited by 304 publications

References 101 publications

Peroxisomes in wild-type and rosy mutant Drosophila melanogaster.

Peroxisomes in wild-type and rosy mutant Drosophila melanogaster.

Localization of nonspecific lipid transfer protein (nsLTP = sterol carrier protein 2) and acyl-CoA oxidase in peroxisomes of pigment epithelial cells of rat retina.

NovelPEX1 coding mutations and 5′ UTR regulatory polymorphisms

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