Biochemical abnormalities in rhizomelic chondrodysplasia punctata

Höefler, Gerald; Hoefler, Sigrid; Watkins, Paul A.; Chen, Winston W.; Moser, Ann B.; Baldwin, Virginia J.; McGillivary, B.; Charrow, Joel; Friedman, Jan M.; Rutledge, Lane; Hashimoto, Takashi; Moser, Hugo W.

doi:10.1016/s0022-3476(88)80689-9

Cited by 125 publications

(72 citation statements)

References 36 publications

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“…SDS-PAGE, immunoblot analysis, and autoradiography were performed as described (39). The molecular sizes of bands on autoradiographs were estimated by comparison to mol wt standards and to immunoblots of normal human liver (16,39). Proteinase K digestion.…”

Section: Methodsmentioning

confidence: 99%

“…Tager et al (1 4), using immunoblot analysis, initially reported that all three enzymes were deficient in postmortem liver samples from Zellweger patients. It was subsequently observed that 0-ketothiolase was present in tissues from some Zellweger patients, but its mol wt was about 3000 D larger than the mature enzyme (15,16). PKetothiolase is one of the few peroxisomal proteins that is known to undergo proteolytic processing; the mature enzyme found in peroxisomes is about 3000 D smaller than the de novo synthesized polypeptide (17).…”

mentioning

confidence: 99%

“…RCDP is a peroxisomal disorder in which peroxisomal structure appears intact, but the peroxisomal steps of plasmalogen synthesis and oxidation of phytanic acid are defective (16,28). In addition, we found that the peroxisomal 0-ketothiolase in RCDP tissues was in unprocessed rather than mature form (1 6); this finding was unexpected because @-oxidation of very long chain fatty acids was normal in these tissues.…”

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confidence: 99%

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Aberrant Subcellular Localization of Peroxisomal 3-Ketoacyl-CoA Thiolase in the Zellweger Syndrome and Rhizomelic Chondrodysplasia Punctata

et al. 1990

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ABSTRACT. Fibroblasts from patients with the inherited disorder Zellweger syndrome have few or no peroxisomes; multiple biochemical processes that normally occur in this organelle are defective. Rhizomelic chondrodysplasia punctata (RCDP) is another inherited disorder in which two unrelated peroxisomal metabolic processes, plasmalogen synthesis and phytanic acid oxidation, are impaired despite the normal appearance of peroxisomal structure. It was previously reported that one of the enzymes of peroxisomal fatty acid ,f3-oxidation, 3-ketoacyl-CoA thiolase (P-ketothiolase), was present in precursor rather than mature form in both of these diseases. Immunofluorescent staining for peroxisomal ,f3-ketothiolase showed the immunoreactivity to be localized in subcellular particles in fibroblasts from both Zellweger syndrome and RCDP patients, even though the former lack normal peroxisomes. Immunoblot studies were performed to determine the subcellular location of the thiolase precursor in fractionated fibroblasts from Zellweger and RCDP patients. In both disorders, thiolase immunoreactivity was detected in subcellular fractions having a lower density than normal peroxisomes and mitochondria, and was resistant to digestion by proteinase K.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Aberrant Subcellular Localization of Peroxisomal 3-Ketoacyl-CoA Thiolase in the Zellweger Syndrome and Rhizomelic Chondrodysplasia Punctata

et al. 1990

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“…Acyl-CoA Synthetase Assays-Acyl-coenzyme A synthetase activity was measured by the method previously described (25) C24:0 ␤-Oxidation-␤-Oxidation activity was measured as previously described (27). Freshly harvested fibroblast cell pellets were resuspended in 0.25 M sucrose, 1 mM Tris-HCl, pH 8.0, 1 mM EDTA and held on ice.…”

Section: Enzyme Assaysmentioning

confidence: 99%

Mouse Very Long-chain Acyl-CoA Synthetase in X-linked Adrenoleukodystrophy

Heinzer¹,

Kemp²,

Lu³

et al. 2002

Journal of Biological Chemistry

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X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder characterized by accumulation of very long-chain fatty acids (VLCFA). This accumulation has been attributed to decreased VLCFA ␤-oxidation and peroxisomal very long-chain acyl-CoA synthetase (VLCS) activity. The X-ALD gene, ABCD1, encodes a peroxisomal membrane ATP binding cassette transporter, ALDP, that is hypothesized to affect VLCS activity in peroxisomes by direct interaction with the VLCS enzyme. Recently, a VLCS gene that encodes a protein with significant sequence identity to known rat and human peroxisomal VLCS protein has been identified in mice. We find that the mouse VLCS gene (Vlcs) encodes an enzyme (Vlcs) with VLCS activity that localizes to peroxisomes and is expressed in X-ALD target tissues. We show that the expression of Vlcs in the peroxisomes of X-ALD mouse fibroblasts improves VLCFA ␤-oxidation in these cells, implying a role for this enzyme in the biochemical abnormality of X-ALD. X-ALD mice, which accumulate VLCFA in tissues, show no change in the expression of Vlcs, the subcellular localization of Vlcs, or general peroxisomal VLCS activity. These observations imply that ALDP is not necessary for the proper expression or localization of Vlcs protein, and the control of VLCFA levels does not depend on the direct interaction of Vlcs and ALDP.

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“…VLCFA levels were elevated in plasma but much less in cultured fibroblasts compared with Zellweger syndrome, n-ALD, or IRD (Table 1) (39)(40)(41). &Oxidation of VLCFA in cultured fibroblasts was decreased (64% of control values) but less than in Zellweger, n-ALD or IRD cells (Table 1) (39)(40)(41). Bile acid intermediates (trihydroxycoprostanoic acid and dihydroxycoprostanoic acid).…”

Section: Aubourg Et /1lmentioning

confidence: 99%

Pseudo Infantile Refsum's Disease: Catalase-Deficient Peroxisomal Particles with Partial Deficiency of Plasmalogen Synthesis and Oxidation of Fatty Acids

et al. 1993

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ABSTRACT. Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum's disease are genetic disorders characterized by the virtual absence of catalasepositive perosisomes and a general impairment of perosisomal functions. Recent studies in these three disorders have provided morphologic evidence of perosisomal "ghosts" of density 1.10 g / c d that contain membrane proteins but lack a majority of the matrix enzyme activities. We report here the biochemical studies in a female infant with clinical features of infantile Refsum's disease whose liver and fibroblasts contained cytosolic catalase but no catalase-positive peroxisomes. Oxidation of phytanic and pipecolic acids was severely impaired, whereas osidation of very-long-chain fatty acids and dihydrosyacetone phosphate acyltransferase activity were only partially decreased. Immunoblot analysis showed that the three peroxisomal &oxidation enzymes (acyl-CoA oxidase, enoyl-CoA hydratasel3-hydrosyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase) were detectable in liver tissues. The 3-ketoacyl-CoA thiolase was of the mature form (41 kD). in contrast with other perosisomal disorders with multipl'i enzyme deficiencies. The majority of these peroxisomal enzvme activities were associated with two subcellular membrane vesicle fractions lacking catalase: one had the density of normal peroxisomes (1.17 g/cm"), the other, yet undescribed, a lower density (1.137 g/cm"). This suggests that perosisomes (density = 1.17 g/cm") and structures with lower density (density = 1.137 g/cm") found in this patient's cultured skin fibroblasts, although lacking catalase, contained functional perosisomal enzymes. This distinguishes this disorder from other disorders of perosisome biogenesis. (Pediatr Res 34: 270-276, 1993) Abbreviations n-ALD, neonatal adrenoleukodystrophy @-ketothiolase or thiolase, 3-ketoacyl-CoA thiolase bifunctional enzyme, enoyl-CoA hydratasel3-hydrosyacylCoA dehydrogenase VLCFA, very-long-chain fatty acid DAB, diaminobenzidine DHAP-AT, dihydroxyacetone phosphate acyltransferase

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Biochemical abnormalities in rhizomelic chondrodysplasia punctata

Cited by 125 publications

References 36 publications

Aberrant Subcellular Localization of Peroxisomal 3-Ketoacyl-CoA Thiolase in the Zellweger Syndrome and Rhizomelic Chondrodysplasia Punctata

Aberrant Subcellular Localization of Peroxisomal 3-Ketoacyl-CoA Thiolase in the Zellweger Syndrome and Rhizomelic Chondrodysplasia Punctata

Mouse Very Long-chain Acyl-CoA Synthetase in X-linked Adrenoleukodystrophy

Pseudo Infantile Refsum's Disease: Catalase-Deficient Peroxisomal Particles with Partial Deficiency of Plasmalogen Synthesis and Oxidation of Fatty Acids

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