Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding Delta1-pyrroline-5-carboxylate synthase
| Autor: | P. Kamoun, Shlomo Almashanu, David Valle, Chien-An Andy Hu, Bernard Aral, Matthias R. Baumgartner, Cassandra Obie, D. Rabier, Gary Steel, Jean-Marie Saudubray |
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| Rok vydání: | 2000 |
| Předmět: |
Adult
Male Ornithine Gene isoform Proline Arginine Ornithine aminotransferase DNA Mutational Analysis CHO Cells Biology Transfection chemistry.chemical_compound Biosynthesis Catalytic Domain Cricetinae Genetics Citrulline Animals Humans Hyperammonemia RNA Messenger Child Amino Acid Metabolism Inborn Errors Molecular Biology Genetics (clinical) chemistry.chemical_classification Ornithine-Oxo-Acid Transaminase General Medicine Fibroblasts Pedigree Amino acid Phenotype Biochemistry chemistry Mutation Female France |
| Zdroj: | Human Molecular Genetics. 9:2853-2858 |
| ISSN: | 1460-2083 |
| DOI: | 10.1093/hmg/9.19.2853 |
| Popis: | delta(1)-pyrroline-5-carboxylate synthase (P5CS), a bifunctional ATP- and NADPH-dependent mitochondrial enzyme, catalyzes the reduction of glutamate to delta(1)-pyrroline-5-carboxylate, a critical step in the biosynthesis of proline, ornithine and arginine. Recently, we reported the cloning and expression of human and murine P5CS cDNAs. Previously, we showed that mammalian P5CS undergoes alternative splicing to generate two isoforms differing only by a 2 amino acid insert at the N-terminus of the gamma-glutamyl kinase active site. The short isoform has high activity in the gut, where it participates in arginine biosynthesis and is inhibited by ornithine. The long isoform, expressed in multiple tissues, is necessary for the synthesis of proline from glutamate and is insensitive to ornithine. Here, we describe a newly recognized inborn error due to the deficiency of P5CS in two siblings with progressive neurodegeneration, joint laxity, skin hyperelasticity and bilateral subcapsular cataracts. Their metabolic phenotype includes hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia. Both are homozygous for the missense mutation, R84Q, which alters a conserved residue in the P5CS gamma-glutamyl kinase domain. R84Q is not present in 194 control chromosomes and dramatically reduces the activity of both P5CS isoforms when expressed in mammalian cells. Additionally, R84Q appears to destabilize the long isoform. This is the first documented report of an inborn error of P5CS and suggests that this disorder should be considered in the differential diagnosis in patients with neurodegeneration and/or cataracts and connective tissue disease. |
| Databáze: | OpenAIRE |
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