The molecular basis of glutamate formiminotransferase deficiency

John F. Hilton, Karen E. Christensen, David Watkins, Benjamin A. Raby, Yannick Renaud, Susanna De la Luna, Xavier P. Estivill, Robert E. MacKenzie, Thomas J. Hudson, David S. Rosenblatt

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)67-73
Number of pages7
JournalHuman Mutation
Volume22
Issue number1
DOIs
Publication statusPublished - 2003
Externally publishedYes

Fingerprint

Mutation
Glutamate Formimidoyltransferase
Phenotype
Histidine
Megaloblastic Anemia
Inborn Errors Metabolism
Missense Mutation
Folic Acid
Mutagenesis
Intellectual Disability
Siblings
Swine
Alleles
Glutamate formiminotransferase deficiency
Urine
Escherichia coli
Polymerase Chain Reaction
Enzymes
Genes
formiminotetrahydrofolate cyclodeaminase

Keywords

  • FIGLU
  • Folate
  • FTCD
  • Glutamate formiminotransferase
  • Inborn error of metabolism

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Hilton, J. F., Christensen, K. E., Watkins, D., Raby, B. A., Renaud, Y., De la Luna, S., ... Rosenblatt, D. S. (2003). The molecular basis of glutamate formiminotransferase deficiency. Human Mutation, 22(1), 67-73. https://doi.org/10.1002/humu.10236

The molecular basis of glutamate formiminotransferase deficiency. / Hilton, John F.; Christensen, Karen E.; Watkins, David; Raby, Benjamin A.; Renaud, Yannick; De la Luna, Susanna; Estivill, Xavier P.; MacKenzie, Robert E.; Hudson, Thomas J.; Rosenblatt, David S.

In: Human Mutation, Vol. 22, No. 1, 2003, p. 67-73.

Research output: Contribution to journalArticle

Hilton, JF, Christensen, KE, Watkins, D, Raby, BA, Renaud, Y, De la Luna, S, Estivill, XP, MacKenzie, RE, Hudson, TJ & Rosenblatt, DS 2003, 'The molecular basis of glutamate formiminotransferase deficiency', Human Mutation, vol. 22, no. 1, pp. 67-73. https://doi.org/10.1002/humu.10236
Hilton JF, Christensen KE, Watkins D, Raby BA, Renaud Y, De la Luna S et al. The molecular basis of glutamate formiminotransferase deficiency. Human Mutation. 2003;22(1):67-73. https://doi.org/10.1002/humu.10236
Hilton, John F. ; Christensen, Karen E. ; Watkins, David ; Raby, Benjamin A. ; Renaud, Yannick ; De la Luna, Susanna ; Estivill, Xavier P. ; MacKenzie, Robert E. ; Hudson, Thomas J. ; Rosenblatt, David S. / The molecular basis of glutamate formiminotransferase deficiency. In: Human Mutation. 2003 ; Vol. 22, No. 1. pp. 67-73.
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