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

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43 Citations (Scopus)


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
Issue number1
Publication statusPublished - 2003
Externally publishedYes



  • 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., Estivill, X. P., MacKenzie, R. E., Hudson, T. J., & Rosenblatt, D. S. (2003). The molecular basis of glutamate formiminotransferase deficiency. Human Mutation, 22(1), 67-73.