Phenylketonuria (PKU) is an autosomal recessive human genetic disorder caused by a deficiency of hepatic phenylalanine hydroxy-lase (PAH, phenylalanine 4-monooxygenase, EC 188.8.131.52). PKU is a common inborn error of amino-acid metabolism in Caucasian populations and approximately 1 in 50 individuals are carriers of a PKU allele1–2. 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 haplotypes3–5. 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 alleles6. 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.
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DiLella, A., Marvi, J., Brayton, K. et al. An ammo-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2. Nature 327, 333–336 (1987). https://doi.org/10.1038/327333a0
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