Rhizomelic chondrodysplasia punctata. Deficiency of 3-oxoacyl-coenzyme A thiolase in peroxisomes and impaired processing of the enzyme.

Heikoop, Judith C.; Roermund, C. W. T. van; Just, Wilhelm W.; Ofman, Rob; Schutgens, R. B. H.; Heymans, H. S. A.; Wanders, Ronald J. A.; Tager, J. M.

doi:10.1172/jci114674

Cited by 57 publications

(30 citation statements)

References 26 publications

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“…Peroxin 7 deficiency, however, leads to mislocalization and cytosolic accumulation of unprocessed PhyH, alkyldihydroxyacetonephosphate synthase (ADHAPS), and peroxisomal 3-oxoacyl-CoA thiolase 1 (thiolase). The difference in molecular weight between the unprocessed precursor and mature proteins can be readily visualized by a mobility shift on immunoblot (Heikoop et al 1990;Swinkels et al 1991). As expected, ADHAPS was found in its mature 67-kDa form in fibroblast homogenates from both a normal control individual and a patient with classic RD with mutations in the PHYH gene ( fig.…”

Section: Figuresupporting

confidence: 55%

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Identification of PEX7 as the Second Gene Involved in Refsum Disease

Brink

Brites

Haasjes

et al. 2003

Advances in Experimental Medicine and Biology

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Patients affected with Refsum disease (RD) have elevated levels of phytanic acid due to a deficiency of the peroxisomal enzyme phytanoyl-CoA hydroxylase (PhyH). In most patients with RD, disease-causing mutations in the PHYH gene have been identified, but, in a subset, no mutations could be found, indicating that the condition is genetically heterogeneous. Linkage analysis of a few patients diagnosed with RD, but without mutations in PHYH, suggested a second locus on chromosome 6q22-24. This region includes the PEX7 gene, which codes for the peroxin 7 receptor protein required for peroxisomal import of proteins containing a peroxisomal targeting signal type 2. Mutations in PEX7 normally cause rhizomelic chondrodysplasia punctata type 1, a severe peroxisomal disorder. Biochemical analyses of the patients with RD revealed defects not only in phytanic acid a-oxidation but also in plasmalogen synthesis and peroxisomal thiolase. Furthermore, we identified mutations in the PEX7 gene. Our data show that mutations in the PEX7 gene may result in a broad clinical spectrum ranging from severe rhizomelic chondrodysplasia punctata to relatively mild RD and that clinical diagnosis of conditions involving retinitis pigmentosa, ataxia, and polyneuropathy may require a full screen of peroxisomal functions.

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Section: Figuresupporting

confidence: 55%

“…Solid and open arrows indicate the position of the unprocessed and mature forms, respectively. Immunoblot analyses were performed, as described, for peroxisomal thiolase (Heikoop et al 1990), ADHAPS (de Vet et al 1997), and PhyH with affinity-purified antibodies (Jansen et al 2000).…”

Section: Figurementioning

confidence: 99%

Identification of PEX7 as the Second Gene Involved in Refsum Disease

Brink

Brites

Haasjes

et al. 2003

Advances in Experimental Medicine and Biology

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“…Triton X-100 for 15 min at room temperature. In some cases, the cells were differentially permeabilised with digitonin (25 Fg/ml) for 5 rnin instead of Triton X-100 (Heikoop et al, 1990;Motley et al, 1994). The cells were then processed for double or single label indirect immunofluorescence using rabbit anti-human AGT and guinea pig antihuman catalase antisera.…”

Section: Methodsmentioning

confidence: 99%

Molecular Basis of the Variable Mitochondrial and Peroxisomal Localisation of Alanine‐Glyoxylate Aminotransferase

Oatey¹,

Lumb²,

Danpure³

1996

European Journal of Biochemistry

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The molecular basis of the variable species-specific peroxisomal andor mitochondrial targeting of the enzyme alanine-glyoxylate aminotransferase 1 (AGT) has been studied in human fibroblasts by confocal immunofluorescence microscopy after intranuclear microinjection of various human, rabbit, marmoset, and feline ACT cDNA constructs. The expression of full-length human and rabbit AGT cDNA led to an exclusively peroxisomal distribution of ACT. However, the distribution of feline and marmoset AGT depended on the cDNA construct injected. In both species, injection of the short cDNAs (from transcripts that occur naturally in marmoset liver but not in feline liver) led to an exclusively peroxisomal distribution. However, injection of the long cDNAs (from transcripts that occur naturally in both species) led to most of the AGT being targeted to the mitochondria and only a small, yet significant, fraction to the peroxisomes. Reintroduction of the 'ancestral' first potential translation initiation site into human AGT cDNA led to an 'ancestral' distribution of AGT (i.e. both mitochondrial and peroxisomal). Deletion of the second potential translation start site from the long feline cDNA led to a distribution that was almost entirely mitochondrial, which suggests that most peroxisomal AGT encoded by the long cDNA results from internal translation initiation from this site with the consequent loss of the N-terminal mitochondrial targeting sequence. Expression of rabbit cDNA and the short marmoset and feline cDNAs in cells selectively deficient in the import of peroxisomal matrix proteins showed that peroxisomal AGT in all these species is imported via the peroxisomal targeting sequence type 1 (PTS1) import pathway. The almost complete functional dominance of the N-terminal mitochondrial targeting sequence over the Cterminal PTS, which was not due to any direct interference of the former with peroxisomal import, was maintained even when the unusual PTSl of AGT (KKL in human) was replaced by the prototypical PTSl SKL. The results demonstrate that the major determinant of alanine-glyoxylate aminotransferase subcellular distribution in mammals is the presence or absence of the mitochondrial targeting sequence rather than the peroxisomal targeting sequence. Various strategies have arisen during the evolution of mammals to enable the exclusion of the mitochondrial targeting sequence from the newly synthesised polypeptide, all of which involve the use of alternative transcription and/or translation initiation sites.

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“…DHAPAT activity (17), C26:0 and pristanic acid ␤-oxidation (18) were assayed in primary skin fibroblasts as previously described. Catalase immunofluorescence (19) and complementation analysis (20) were performed as described before. To allow complementation analysis in the cells of patient 2, we cultured these at 40°C for 3 d after fusion of the cells.…”

Section: Subjectsmentioning

confidence: 99%