title: An amino-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2.
abstract: Phenylketonuria (PKU) is an autosomal recessive human genetic disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH, phenylalanine 4-monooxygenase, EC 1.14.16.1). PKU is a common inborn error of amino-acid metabolism in caucasian populations and approximately 1 in 50 individuals are carriers of a PKU allele. To define the molecular basis of PKU, we characterized twelve restriction fragment-length polymorphism (RFLP) haplotypes of the PAH locus in the northern European population and observed that 90% of the PKU alleles in this population are confined to four common RFLP haplotypes. We have recently reported a splicing mutation in the PAH gene that is associated with RFLP haplotype 3 which is present at about 40% of mutant alleles. We now report the molecular lesion associated with the RFLP haplotype 2 mutant allele. This defect is caused by a C-to-T transition in exon 12 resulting in an amino-acid substitution (Arg to Trp) at residue 408 of PAH. Direct hybridization analysis of the point mutation using a specific oligonucleotide probe demonstrated that this mutation is also in linkage disequilibrium with RFLP haplotype 2 alleles that make up about 20% of mutant PAH genes.
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D004247:DNA / Q000235:genetics*; D005060:Europe; D006239:Haplotypes; D006801:Humans; D009154:Mutation; D009693:Nucleic Acid Hybridization; D010651:Phenylalanine Hydroxylase / Q000172:deficiency / Q000235:genetics; D010661:Phenylketonurias / Q000235:genetics*; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length
chemical_list: D004247:DNA; D010651:Phenylalanine Hydroxylase