The molecular basis of glutamate formiminotransferase deficiency

Authors

  • John F. Hilton,

    1. Department of Biology, McGill University, Montreal, Quebec, Canada
    2. Division of Medical Genetics, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
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  • Karen E. Christensen,

    1. Department of Biochemistry, McGill University, Montreal, Quebec, Canada
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  • David Watkins,

    1. Division of Medical Genetics, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
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  • Benjamin A. Raby,

    1. Montreal Genome Centre, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
    2. Department of Medicine, McGill University, Montreal, Quebec, Canada
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  • Yannick Renaud,

    1. Montreal Genome Centre, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
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  • Susanna de la Luna,

    1. Genomics Regulation Center, Barcelona, Spain
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  • Xavier Estivill,

    1. Genomics Regulation Center, Barcelona, Spain
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  • Robert E. MacKenzie,

    1. Department of Biochemistry, McGill University, Montreal, Quebec, Canada
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  • Thomas J. Hudson,

    1. Division of Medical Genetics, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
    2. Montreal Genome Centre, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
    3. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
    4. Department of Medicine, McGill University, Montreal, Quebec, Canada
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  • David S. Rosenblatt

    Corresponding author
    1. Department of Biology, McGill University, Montreal, Quebec, Canada
    2. Division of Medical Genetics, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada
    3. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
    4. Department of Medicine, McGill University, Montreal, Quebec, Canada
    5. Department of Pediatrics, McGill University, Montreal, Quebec, Canada
    • Division of Medical Genetics, Room H5-63, McGill University Health Centre/Royal Victoria Hospital Site, 687 Pine Avenue West, Montreal, Quebec, H3A 1A1
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  • Communicated by R. Garry Cutting

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. Hum Mutat 22:67–73, 2003. © 2003 Wiley-Liss, Inc.

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