Linked Life Data

11092761

Source:http://linkedlifedata.com/resource/pubmed/id/11092761

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
19
pubmed:dateCreated
2001-1-3
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0964-6906
pubmed:author
pubmed:issnType
Print
pubmed:day
22
pubmed:volume
9
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2853-8
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed-meshheading:11092761-Adult, pubmed-meshheading:11092761-Amino Acid Metabolism, Inborn Errors, pubmed-meshheading:11092761-Animals, pubmed-meshheading:11092761-Arginine, pubmed-meshheading:11092761-CHO Cells, pubmed-meshheading:11092761-Catalytic Domain, pubmed-meshheading:11092761-Child, pubmed-meshheading:11092761-Citrulline, pubmed-meshheading:11092761-Cricetinae, pubmed-meshheading:11092761-DNA Mutational Analysis, pubmed-meshheading:11092761-Female, pubmed-meshheading:11092761-Fibroblasts, pubmed-meshheading:11092761-France, pubmed-meshheading:11092761-Humans, pubmed-meshheading:11092761-Hyperammonemia, pubmed-meshheading:11092761-Male, pubmed-meshheading:11092761-Mutation, pubmed-meshheading:11092761-Ornithine, pubmed-meshheading:11092761-Ornithine-Oxo-Acid Transaminase, pubmed-meshheading:11092761-Pedigree, pubmed-meshheading:11092761-Phenotype, pubmed-meshheading:11092761-Proline, pubmed-meshheading:11092761-RNA, Messenger, pubmed-meshheading:11092761-Transfection
pubmed:year
2000
pubmed:articleTitle
Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding delta(1)-pyrroline-5-carboxylate synthase.
pubmed:affiliation
Department of Pediatrics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't