The PAH gene, phenylketonuria, and a paradigm shift


  • Charles R. Scriver

    Corresponding author
    1. Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
    2. Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
    3. Department of Pediatrics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
    4. Department of Biology, Faculty of Science, McGill University, Montreal, Quebec, Canada
    • DeBelle Laboratory for Biochemical Genetics, Rm. A-717, Montreal Children's Hospital Research Institute, 2300 Tupper Street, Montreal, Quebec H3H 1P3, Canada
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  • Communicated by Johannes Zschocke

  • This article is a US Government work and, as such, is in the public domain in the United States of America.


“Inborn errors of metabolism,” first recognized 100 years ago by Garrod, were seen as transforming evidence for chemical and biological individuality. Phenylketonuria (PKU), a Mendelian autosomal recessive phenotype, was identified in 1934 by Asbjörn Fölling. It is a disease with impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia (HPA). Its metabolic phenotype is accountable to multifactorial origins both in nurture, where the normal nutritional experience introduces L-phenylalanine, and in nature, where mutations (>500 alleles) occur in the phenylalanine hydroxylase gene (PAH) on chromosome 12q23.2 encoding the L-phenylalanine hydroxylase enzyme (EC The PAH enzyme converts phenylalanine to tyrosine in the presence of molecular oxygen and catalytic amounts of tetrahydrobiopterin (BH4), its nonprotein cofactor. PKU is among the first of the human genetic diseases to enter, through newborn screening, the domain of public health, and to show a treatment effect. This effect caused a paradigm shift in attitudes about genetic disease. The PKU story contains many messages, including: a framework on which to appreciate the complexity of PKU in which phenotype reflects both locus-specific and genomic components; what the human PAH gene tells us about human population genetics and evolution of modern humans; and how our interest in PKU is served by a locus-specific mutation database (; last accessed 20 March 2007). The individual Mendelian PKU phenotype has no “simple” or single explanation; every patient has her/his own complex PKU phenotype and will be treated accordingly. Knowledge about PKU reveals genomic components of both disease and health. Hum Mutat 28(9), 831–845, 2007. Published 2007 Wiley-Liss, Inc.