title: CpG methylation accounts for a recurrent mutation (c.1222C>T) in the human PAH gene.
abstract: The human PAH gene (GenBank: U49897.1 (cDNA), AF404777 (gDNA)) harbors alleles that either cause or are associated with hyperphenylalaninemia and phenylketonuria (http://www.pahdb.mcgill.ca). Mutation analysis has identified approximately 500 alleles of which approximately 30 produce polymorphic core haplotypes. The c.1222C>T allele (p.R408W) is the most prevalent and widely encountered PKU-causing allele. Because it occurs on multiple locus-specific polymorphic haplotypes, it is probably not identical by descent in different populations. This mutation involves a CpG dinucleotide in a so-called "hypermutable" codon suggesting that c.1222C>T could be a recurrent allele following spontaneous methylation-mediated deamination of 5 mC. This concept is widely assumed and accepted but the 5mC status of hypermutable codons has seldom been confirmed. We show that the PAH c.1222C nucleotide is indeed methylated (c.1222 mC) in somatic genomes (leukocyte and brain) of H. sapiens. Examination of a representative region in exon 12 (and also in exon 7) in the PAH gene shows that 5 mC is restricted to cytosines in CpG dinucleotides in the hypermutable codons. The methylation pattern seen in human PAH exon 12 was also observed in the corresponding codon in three nonhuman primates. The finding offers at least one explanation for the high relative frequency of the c.1222C>T (p.R408W) allele in the human population.
authors.affiliation: Molecular Genetics Unit, Department of Biology and Division of Medical Genetics, The University of Western Ontario, London, Ontario, Canada.
authors.forename: B C
authors.initials: BC
authors.lastname: Murphy
authors.forename: C R
authors.initials: CR
authors.lastname: Scriver
authors.forename: S M
authors.initials: SM
authors.lastname: Singh
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D018899:CpG Islands; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005091:Exons; D005787:Gene Frequency; D006801:Humans; D008252:Macaca fascicularis; D008969:Molecular Sequence Data; D002679:Pan troglodytes; D010215:Papio; D010651:Phenylalanine Hydroxylase / Q000235:genetics*; D010661:Phenylketonurias / Q000235:genetics; D017354:Point Mutation
chemical_list: D010651:Phenylalanine Hydroxylase