13 results on '"Chondrodysplasia Punctata, Rhizomelic enzymology"'
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2. Homeostasis of phospholipids - The level of phosphatidylethanolamine tightly adapts to changes in ethanolamine plasmalogens.
- Author
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Dorninger F, Brodde A, Braverman NE, Moser AB, Just WW, Forss-Petter S, Brügger B, and Berger J
- Subjects
- Acyltransferases genetics, Adaptation, Physiological, Animals, Arachidonic Acid metabolism, Cells, Cultured, Chondrodysplasia Punctata, Rhizomelic genetics, Disease Models, Animal, Docosahexaenoic Acids metabolism, Genetic Predisposition to Disease, Homeostasis, Humans, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Severity of Illness Index, Acyltransferases deficiency, Chondrodysplasia Punctata, Rhizomelic enzymology, Fibroblasts enzymology, Gray Matter enzymology, Phosphatidylethanolamines metabolism, Plasmalogens metabolism
- Abstract
Ethanolamine plasmalogens constitute a group of ether glycerophospholipids that, due to their unique biophysical and biochemical properties, are essential components of mammalian cellular membranes. Their importance is emphasized by the consequences of defects in plasmalogen biosynthesis, which in humans cause the fatal disease rhizomelic chondrodysplasia punctata (RCDP). In the present lipidomic study, we used fibroblasts derived from RCDP patients, as well as brain tissue from plasmalogen-deficient mice, to examine the compensatory mechanisms of lipid homeostasis in response to plasmalogen deficiency. Our results show that phosphatidylethanolamine (PE), a diacyl glycerophospholipid, which like ethanolamine plasmalogens carries the head group ethanolamine, is the main player in the adaptation to plasmalogen insufficiency. PE levels were tightly adjusted to the amount of ethanolamine plasmalogens so that their combined levels were kept constant. Similarly, the total amount of polyunsaturated fatty acids (PUFAs) in ethanolamine phospholipids was maintained upon plasmalogen deficiency. However, we found an increased incorporation of arachidonic acid at the expense of docosahexaenoic acid in the PE fraction of plasmalogen-deficient tissues. These data show that under conditions of reduced plasmalogen levels, the amount of total ethanolamine phospholipids is precisely maintained by a rise in PE. At the same time, a shift in the ratio between ω-6 and ω-3 PUFAs occurs, which might have unfavorable, long-term biological consequences. Therefore, our findings are not only of interest for RCDP but may have more widespread implications also for other disease conditions, as for example Alzheimer's disease, that have been associated with a decline in plasmalogens., (Copyright © 2014. Published by Elsevier B.V.)
- Published
- 2015
- Full Text
- View/download PDF
3. Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3.
- Author
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Itzkovitz B, Jiralerspong S, Nimmo G, Loscalzo M, Horovitz DD, Snowden A, Moser A, Steinberg S, and Braverman N
- Subjects
- Acyltransferases metabolism, Alkyl and Aryl Transferases metabolism, Base Sequence, Cell Line, Child, Child, Preschool, Chondrodysplasia Punctata, Rhizomelic enzymology, DNA Mutational Analysis, Female, Genetic Association Studies, Humans, Male, Molecular Sequence Data, Pedigree, Peroxisomes genetics, Peroxisomes metabolism, Plasmalogens genetics, Plasmalogens metabolism, RNA, Messenger biosynthesis, Severity of Illness Index, Acyltransferases genetics, Alkyl and Aryl Transferases genetics, Chondrodysplasia Punctata, Rhizomelic genetics, Mutation
- Abstract
Rhizomelic chondrodysplasia punctata (RCDP) is a disorder of peroxisome metabolism resulting from a deficiency of plasmalogens, a specialized class of membrane phospholipids. Classically, patients have a skeletal dysplasia and profound mental retardation, although milder phenotypes are increasingly being identified. It is commonly caused by defects in the peroxisome transporter, PEX7 (RCDP1), and less frequently due to defects in the peroxisomal enzymes required to initiate plasmalogen synthesis, GNPAT (RCDP2) and AGPS (RCDP3). PEX7 transports AGPS into the peroxisome, where AGPS and GNPAT partner on the luminal membrane surface. The presence of AGPS is thought to be required for GNPAT activity. We present six additional probands with RCDP2 and RCDP3, and the novel mutations identified in them. Using cell lines from these and previously reported patients, we compared the amounts of both AGPS and GNPAT proteins present for the first time. We used protein modeling to predict the structural consequences of AGPS mutations and transcript analysis to predict consequences of GNPAT mutations, and show that milder RCDP phenotypes are likely to be associated with residual protein function. In addition, we propose that full GNPAT activity depends not only on the presence of AGPS, but also on the integrity of substrate channeling from GNPAT to AGPS., (© 2011 Wiley Periodicals, Inc.)
- Published
- 2012
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4. The crucial step in ether phospholipid biosynthesis: structural basis of a noncanonical reaction associated with a peroxisomal disorder.
- Author
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Razeto A, Mattiroli F, Carpanelli E, Aliverti A, Pandini V, Coda A, and Mattevi A
- Subjects
- Alkyl and Aryl Transferases chemistry, Alkyl and Aryl Transferases genetics, Alkyl and Aryl Transferases metabolism, Amino Acid Sequence, Amino Acid Substitution, Animals, Binding Sites, Catalysis, Chondrodysplasia Punctata, Rhizomelic enzymology, Chondrodysplasia Punctata, Rhizomelic metabolism, Chondrodysplasia Punctata, Rhizomelic pathology, Conserved Sequence, Crystallography, X-Ray, Dictyostelium enzymology, Dimerization, Flavin-Adenine Dinucleotide chemistry, Flavin-Adenine Dinucleotide metabolism, Histidine metabolism, Humans, Hydrogen Bonding, Models, Biological, Models, Chemical, Models, Molecular, Molecular Sequence Data, Molecular Structure, Peroxisomal Disorders genetics, Phenylalanine metabolism, Phospholipid Ethers chemistry, Protein Binding, Protein Conformation, Protein Structure, Secondary, Protein Structure, Tertiary, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Sequence Homology, Amino Acid, Spectrum Analysis, Raman, Substrate Specificity, Tyrosine metabolism, Lipid Metabolism, Inborn Errors, Peroxisomal Disorders enzymology, Phospholipid Ethers metabolism
- Abstract
Ether phospholipids are essential constituents of eukaryotic cell membranes. Rhizomelic chondrodysplasia punctata type 3 is a severe peroxisomal disorder caused by inborn deficiency of alkyldihydroxyacetonephosphate synthase (ADPS). The enzyme carries out the most characteristic step in ether phospholipid biosynthesis: formation of the ether bond. The crystal structure of ADPS from Dictyostelium discoideum shows a fatty-alcohol molecule bound in a narrow hydrophobic tunnel, specific for aliphatic chains of 16 carbons. Access to the tunnel is controlled by a flexible loop and a gating helix at the protein-membrane interface. Structural and mutagenesis investigations identify a cluster of hydrophilic catalytic residues, including an essential tyrosine, possibly involved in substrate proton abstraction, and the arginine that is mutated in ADPS-deficient patients. We propose that ether bond formation might be orchestrated through a covalent imine intermediate with the flavin, accounting for the noncanonical employment of a flavin cofactor in a nonredox reaction.
- Published
- 2007
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5. MR imaging and MR spectroscopy in rhizomelic chondrodysplasia punctata.
- Author
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Viola A, Confort-Gouny S, Ranjeva JP, Chabrol B, Raybaud C, Vintila F, and Cozzone PJ
- Subjects
- Chondrodysplasia Punctata, Rhizomelic diagnosis, Chondrodysplasia Punctata, Rhizomelic enzymology, Humans, Infant, Newborn, Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy, Male, Plasmalogens biosynthesis, Acyltransferases deficiency, Brain metabolism, Chondrodysplasia Punctata, Rhizomelic metabolism
- Abstract
A case of rhizomelic chondrodysplasia punctata was investigated with MR imaging of the brain and hydrogen-1 MR spectroscopy of the brain and blood. Areas with abnormal signal hyperintensity on T2-weighted images or hypointensity on T1-weighted images were detected in the subcortical white matter. MR spectroscopy of the brain showed that normal-appearing white matter was characterized by increased levels of mobile lipids and myo-inositol, reduced levels of choline, and the presence of acetate. The importance of these metabolic anomalies is correlated to the deficiency in plasmalogen biosynthesis.
- Published
- 2002
6. Mutational spectrum in the PEX7 gene and functional analysis of mutant alleles in 78 patients with rhizomelic chondrodysplasia punctata type 1.
- Author
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Motley AM, Brites P, Gerez L, Hogenhout E, Haasjes J, Benne R, Tabak HF, Wanders RJ, and Waterham HR
- Subjects
- Amino Acid Sequence, Animals, COS Cells, Chondrodysplasia Punctata, Rhizomelic classification, Chondrodysplasia Punctata, Rhizomelic enzymology, Chondrodysplasia Punctata, Rhizomelic pathology, Codon genetics, DNA Mutational Analysis, Fibroblasts, Frameshift Mutation genetics, Genes, Recessive genetics, Genes, Reporter genetics, Genetic Complementation Test, Homozygote, Humans, Luciferases genetics, Luciferases metabolism, Molecular Sequence Data, Open Reading Frames genetics, Peroxisomal Targeting Signal 2 Receptor, Phenotype, Protein Folding, Protein Structure, Secondary, Receptors, Cytoplasmic and Nuclear chemistry, Repetitive Sequences, Amino Acid genetics, Sequence Alignment, Structure-Activity Relationship, Alleles, Chondrodysplasia Punctata, Rhizomelic genetics, Mutation genetics, Receptors, Cytoplasmic and Nuclear genetics, Receptors, Cytoplasmic and Nuclear metabolism
- Abstract
Rhizomelic chondrodysplasia punctata (RCDP) is a genetically heterogeneous, autosomal recessive disorder of peroxisomal metabolism that is clinically characterized by symmetrical shortening of the proximal long bones, cataracts, periarticular calcifications, multiple joint contractures, and psychomotor retardation. Most patients with RCDP have mutations in the PEX7 gene encoding peroxin 7, the cytosolic PTS2-receptor protein required for targeting a subset of enzymes to peroxisomes. These enzymes are deficient in cells of patients with RCDP, because of their mislocalization to the cytoplasm. We report the mutational spectrum in the PEX7 gene of 78 patients (including five pairs of sibs) clinically and biochemically diagnosed with RCDP type I. We found 22 different mutations, including 18 novel ones. Furthermore, we show by functional analysis that disease severity correlates with PEX7 allele activity: expression of eight different alleles from patients with severe RCDP failed to restore the targeting defect in RCDP fibroblasts, whereas two alleles found only in patients with mild disease complemented the targeting defect upon overexpression. Surprisingly, one of the mild alleles comprises a duplication of nucleotides 45-52, which is predicted to lead to a frameshift at codon 17 and an absence of functional peroxin 7. The ability of this allele to complement the targeting defect in RCDP cells suggests that frame restoration occurs, resulting in full-length functional peroxin 7, which leads to amelioration of the predicted severe phenotype. This was confirmed in vitro by expression of the eight-nucleotide duplication-containing sequence fused in different reading frames to the coding sequence of firefly luciferase in COS cells.
- Published
- 2002
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7. Etherphospholipid biosynthesis and dihydroxyactetone-phosphate acyltransferase: resolution of the genomic organization of the human gnpat gene and its use in the identification of novel mutations.
- Author
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Ofman R, Lajmir S, and Wanders RJ
- Subjects
- Acyltransferases metabolism, Base Sequence, Chondrodysplasia Punctata, Rhizomelic enzymology, Chondrodysplasia Punctata, Rhizomelic genetics, DNA Primers, DNA, Complementary, Humans, Molecular Sequence Data, Polymorphism, Genetic, Acyltransferases genetics, Mutation, Phospholipids biosynthesis
- Abstract
Etherphospholipids are characterised by the occurrence of an alkyl- or alkenyl-group at the sn-1 position of the glycerol backbone. Peroxisomes play an essential role in the formation of etherphospholipids since the first two enzymes of the biosynthetic pathway are strictly peroxisomal. The function of plasmalogens is still an enigma but the recent identification of patients suffering from an isolated defect in either dihydroxyacetone phosphate acyltransferase (GNPAT) or alkyldihydroxyacetone phosphate synthase provides conclusive evidence that plasmalogens play an essential role for human survival and functioning. In this paper we report the complete genomic organisation of the GNPAT gene coding for the peroxisomal dihydroxyacetone phosphate acyltransferase. The gene is located on chromosome 1q42.12-43. It spans approximately 28 kb and consists of 16 exons and 15 introns. This information was used to analyse the GNPAT gene in 12 patients with GNPAT deficiency. All patients analysed were found to have mutations in their GNPAT gene. Of the 9 different mutations found, 2 were missense mutations, 2 small deletions, 1 insertion and 3 mutations were within splice donor/acceptor-sites. Another mutation created an alternative splice donor-site causing the partial deletion of an exon. The data obtained provide conclusive evidence for the major role of GNPAT in etherphospholipid biosynthesis., (Copyright 2001 Academic Press.)
- Published
- 2001
- Full Text
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8. Ether lipid biosynthesis: alkyl-dihydroxyacetonephosphate synthase protein deficiency leads to reduced dihydroxyacetonephosphate acyltransferase activities.
- Author
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de Vet EC, Ijlst L, Oostheim W, Dekker C, Moser HW, van Den Bosch H, and Wanders RJ
- Subjects
- Acyltransferases metabolism, Adult, Alkyl and Aryl Transferases deficiency, Child, Preschool, Chondrodysplasia Punctata, Rhizomelic enzymology, Chondrodysplasia Punctata, Rhizomelic pathology, Female, Humans, Male, Phospholipid Ethers metabolism, Plasmalogens biosynthesis
- Abstract
Recent studies have indicated that two peroxisomal enzymes involved in ether lipid synthesis, i.e., dihydroxyacetonephosphate acyltransferase and alkyl-dihydroxyacetonephosphate synthase, are directed to peroxisomes by different targeting signals, i.e., peroxisomal targeting signal type 1 and type 2, respectively. In this study, we describe a new human fibroblast cell line in which alkyl-dihydroxyacetonephosphate synthase was found to be deficient both at the level of enzyme activity and enzyme protein. At the cDNA level, a 128 base pair deletion was found leading to a premature stop. Remarkably, dihydroxyacetonephosphate acyltransferase activity was strongly reduced to a level comparable to the activities measured in fibroblasts from patients affected by the classical form of rhizomelic chondrodysplasia punctata (caused by a defect in peroxisomal targeting signal type 2 import). Dihydroxyacetonephosphate acyltransferase activity was completely normal in another alkyl-dihydroxyacetonephosphate synthase activity-deficient patient. Fibroblasts from this patient showed normal levels of the synthase protein and inactivity results from a point mutation leading to an amino acid substitution. These results strongly suggest that the activity of dihydroxyacetonephosphate acyltransferase is dependent on the presence of alkyl-dihydroxyacetonephosphate synthase protein. This interpretation implies that the deficiency of dihydroxyacetonephosphate acyltransferase (targeted by a peroxisomal targeting signal type 1) in the classic form of rhizomelic chondrodysplasia punctata is a consequence of the absence of the alkyl-dihydroxyacetonephosphate synthase protein (targeted by a peroxisomal targeting signal type 2).
- Published
- 1999
9. Prenatal diagnosis of rhizomelic chondrodysplasia punctata due to isolated alkyldihydroacetonephosphate acyltransferase synthase deficiency.
- Author
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Brookhyser KM, Lipson MH, Moser AB, Moser HW, Lachman RS, and Rimoin DL
- Subjects
- Adult, Amniocentesis, Cartilage pathology, Chondrodysplasia Punctata, Rhizomelic pathology, Female, Fibroblasts ultrastructure, Gestational Age, Humans, Karyotyping, Male, Microbodies metabolism, Plasmalogens biosynthesis, Plasmalogens blood, Pregnancy, Ultrasonography, Prenatal, Alkyl and Aryl Transferases deficiency, Chondrodysplasia Punctata, Rhizomelic diagnosis, Chondrodysplasia Punctata, Rhizomelic enzymology, Prenatal Diagnosis methods
- Abstract
Current practices in prenatal diagnosis of rhizomelic chondrodysplasia punctata (RCDP) are reviewed. A case is presented with a family having one daughter affected with RCDP due to alkyldihydroacetonephosphate acyltransferase synthase (DHAPAT synthase) deficiency, and three subsequent pregnancies. Biochemical test values are presented for the pregnancies and daughter. Post-mortem tests of one fetus of a terminated pregnancy showed that radiologic examination could not make the diagnosis of RCDP. We conclude that biochemical or molecular testing is necessary to accurately diagnose this type of RCDP prenatally.
- Published
- 1999
- Full Text
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10. Cholesterol biosynthesis, peroxisomes and peroxisomal disorders: mevalonate kinase is not only deficient in Zellweger syndrome but also in rhizomelic chondrodysplasia punctata.
- Author
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Wanders RJ and Romeijn GJ
- Subjects
- Cells, Cultured, Fibroblasts enzymology, Humans, Microbodies, Peroxisomal Disorders enzymology, Cholesterol biosynthesis, Chondrodysplasia Punctata, Rhizomelic enzymology, Phosphotransferases (Alcohol Group Acceptor) deficiency, Zellweger Syndrome enzymology
- Published
- 1998
- Full Text
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11. Acyl-CoA:dihydroxyacetonephosphate acyltransferase: cloning of the human cDNA and resolution of the molecular basis in rhizomelic chondrodysplasia punctata type 2.
- Author
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Ofman R, Hettema EH, Hogenhout EM, Caruso U, Muijsers AO, and Wanders RJ
- Subjects
- Acyltransferases biosynthesis, Amino Acid Sequence, Animals, Base Sequence, DNA Mutational Analysis, DNA, Complementary isolation & purification, Female, Humans, Male, Mice, Molecular Sequence Data, Saccharomyces cerevisiae enzymology, Saccharomyces cerevisiae genetics, Acyltransferases genetics, Chondrodysplasia Punctata, Rhizomelic enzymology, Chondrodysplasia Punctata, Rhizomelic genetics
- Abstract
Rhizomelic chondrodysplasia punctata (RCDP) is a genetic disorder which is clinically characterized by rhizomelic shortening of the upper extremities, typical dysmorphic facial appearance, congenital contractures and severe growth and mental retardation. Patients with RCDP can be subdivided into three subgroups based on biochemical analyses and complementation studies. The largest subgroup contains patients with mutations in the PEX7 gene encoding the PTS2 receptor. This results in multiple peroxisomal abnormalities which includes a deficiency of acyl-CoA:dihydroxyacetonephosphate acyltransferase (DHAPAT), alkyl-dihydroxyacetonephosphate synthase (alkyl-DHAP synthase), peroxisomal 3-ketoacyl-CoA thiolase and phytanoyl-CoA hydroxylase, although there are differences in the extent of the deficiencies observed. Patients in the two other subgroups have been reported to be either deficient in the activity of DHAPAT (RCDP type 2) or alkyl-DHAP synthase (RCDP type 3) while no other abnormalities could be observed. To examine whether the gene encoding DHAPAT is mutated in patients with RCDP type 2, we determined the N-terminal amino acid sequence of the enzyme isolated from human placenta. Using this sequence as a query, we identified a 2040 bp open reading frame (ORF) in the human database of expressed sequence tags. Expression of this ORF in the yeast Saccharomyces cerevisiae showed that we have identified the DHAPAT cDNA. The deduced amino acid sequence revealed no PTS2 consensus sequence. In contrast DHAPAT appears to contain a putative PTS1 at the extreme C-terminus. All RCDP type 2 patients analyzed were found to contain mutations in their DHAPAT cDNA. This demonstrates that RCDP type 2 is the result of mutations in DHAPAT.
- Published
- 1998
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12. Phytanoyl-CoA hydroxylase is not only deficient in classical Refsum disease but also in rhizomelic chondrodysplasia punctata.
- Author
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Jansen GA, Mihalik SJ, Watkins PA, Moser HW, Jakobs C, Heijmans HS, and Wanders RJ
- Subjects
- Fluorescent Antibody Technique, Indirect, Humans, Liver enzymology, Chondrodysplasia Punctata, Rhizomelic enzymology, Mixed Function Oxygenases deficiency, Peroxisomal Disorders enzymology
- Published
- 1997
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13. Isolated dihydroxyacetonephosphate-acyl-transferase deficiency in rhizomelic chondrodysplasia punctata: clinical presentation, metabolic and histological findings.
- Author
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Hebestreit H, Wanders RJ, Schutgens RB, Espeel M, Kerckaert I, Roels F, Schmausser B, Schrod L, and Marx A
- Subjects
- Autopsy, Chondrodysplasia Punctata, Rhizomelic metabolism, Chondrodysplasia Punctata, Rhizomelic pathology, Humans, Immunohistochemistry, Infant, Newborn, Kidney metabolism, Kidney pathology, Liver metabolism, Liver pathology, Male, Microbodies ultrastructure, Acyltransferases deficiency, Chondrodysplasia Punctata, Rhizomelic enzymology
- Abstract
Unlabelled: Rhizomelic chondrodysplasia punctata (RCDP) is clinically characterized by symmetrical shortening of the proximal limbs, contractures of joints, a characteristic dysmorphic face, and cataracts. In the classical form an impairment of several peroxisomal functions and enzymes (plasmalogen synthesis, phytanic acid oxidation, 3-oxoacyl-CoA thiolase) has been repeatedly shown. Recently a variant involving only the peroxisomal dihydroxyacetonephosphate acyltransferase (DHAP-AT) has been described. We present a patient with isolated DHAP-AT deficiency and all clinical, radiological and pathological features of classical RCDP. For the first time, microscopy and immunocytochemistry of hepatocytes could be performed., Conclusion: In contrast to studies on classical rhizomelic chondrodysplasia punctata which have shown enlarged peroxisomes in numbers varying from hepatocyte to hepatocyte, the peroxisomes in our patient seem to be normal in size, number and shape.
- Published
- 1996
- Full Text
- View/download PDF
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