title: The molecular basis of glutamate formiminotransferase deficiency.
abstract: Glutamate formiminotransferase deficiency, an autosomal recessive disorder and the second most common inborn error of folate metabolism, is presumed to be due to defects in the bifunctional enzyme glutamate formiminotransferase-cyclodeaminase (FTCD). Features of a severe phenotype, first identified in patients of Japanese descent, include elevated levels of formiminoglutamate (FIGLU) in the urine in response to histidine administration, megaloblastic anemia, and mental retardation. Features of a mild phenotype include high urinary excretion of FIGLU in the absence of histidine administration, mild developmental delay, and no hematological abnormalities. We found mutations in the human FTCD gene in three patients with putative glutamate formiminotransferase deficiency. Two siblings were heterozygous for missense mutations, c.457C>T (R135C) and c.940G>C (R299P). Mutagenesis of porcine FTCD and expression in E. coli showed that the R135C mutation reduced formiminotransferase activity to 61% of wild-type, whereas the R299P mutation reduced this activity to 57% of wild-type. The third patient was hemizygous for c.1033insG, with quantitative PCR indicating that the other allele contained a deletion. These mutations are the first identified in glutamate formiminotransferase deficiency and demonstrate that mutations in FTCD represent the molecular basis for the mild phenotype of this disease.
authors.affiliation: Department of Biology, McGill University, Montreal, Quebec, Canada.
authors.forename: John F
authors.initials: JF
authors.lastname: Hilton
authors.forename: Karen E
authors.initials: KE
authors.lastname: Christensen
authors.forename: David
authors.initials: D
authors.lastname: Watkins
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Raby
authors.forename: Yannick
authors.initials: Y
authors.lastname: Renaud
authors.forename: Susanna
authors.initials: S
authors.lastname: de la Luna
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Robert E
authors.initials: RE
authors.lastname: MacKenzie
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudson
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
mesh_terms: D000642:Ammonia-Lyases / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D051042:Glutamate Formimidoyltransferase; D006801:Humans; D019877:Hydroxymethyl and Formyl Transferases / Q000172:deficiency* / Q000235:genetics*; D008661:Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics; D009097:Multienzyme Complexes; D064251:Multifunctional Enzymes; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction / Q000379:methods; D017422:Sequence Analysis, DNA / Q000379:methods; D013552:Swine
chemical_list: D009097:Multienzyme Complexes; D064251:Multifunctional Enzymes; D019877:Hydroxymethyl and Formyl Transferases; C494848:FTCD protein, human; D051042:Glutamate Formimidoyltransferase; D000642:Ammonia-Lyases; C020148:formiminotetrahydrofolate cyclodeaminase