AUTOMATED SEQUENCING DETECTS ALL MUTATIONS IN NORTHERN IRISH PATIENTSWITH PHENYLKETONURIA AND MILD HYPERPHENYLALANINEMIA

In the first phase of the Northern Ireland PKU Study, we used automate d sequencing to identify the spectrum of mutations in a random group o f 32 unrelated phenylketonuria (PKU) families. We also investigated 7 Northern Irish patients with mild hyperphenylalaninaemia not requiring dietary intervention (MHP, previously referred to as non-PKU HPA). Di sease-causing mutations were identified on all 78 investigated chromos omes. We found 23 different mutations, including 20 missense, 1 nonsen se and 2 splice site mutations. All mutations were located within exon s or at intron-exon boundaries of the phenylalanine hydroxylase gene. Seven mutations occurred at CpG sites, confirming these sites as mutat ion hot-spots in PKU. Mutations R408W and I65T are the two commonest P KU mutations in the Northern Irish population. Two mutations (T380M an d V245A) can be characterized as MHP mutations; they are quasi dominan t markers for MHP since they cause mild hyperphenylalaninaemia even wh en occurring in conjunction with the most severe PKU mutations. The re sults have proven valuable for the development of a routine PKU mutati on analysis system in Northern Ireland.