PHENYLALANINE-HYDROXYLASE GENE-MUTATIONS IN THE UNITED-STATES - REPORT FROM THE MATERNAL PKU COLLABORATIVE STUDY

The major cause of hyperphenylalaninemia is mutations in the gene enco ding phenylalanine hydroxylase (PAH). The lino,vn mutations have been identified primarily in European patients. The purpose of this study w as to determine the spectrum of mutations responsible for PAH deficien cy in the United States. One hundred forty-nine patients enrolled in t he Maternal PKU Collaborative Study were subjects for clinical and mol ecular investigations. PAH gene mutations associated with phenylketonu ria (PKU) or mild hyperphenylalaninemia (MHP) were identified on 279 o f 294 independent mutant chromosomes, a diagnostic efficiency of 95%. The spectrum is composed of 71 different mutations, including 47 misse nse mutations, 11 splice mutations, 5 nonsense mutations, and 8 microd eletions. Sixteen previously unreported mutations were identified. Amo ng the novel mutations, five were found in patients with MHP, and the remainder were found in patients with PKU. The most common mutations w ere R408W, IVS12nt1g-->a, and Y414C, accounting for 18.7%, 7.8%, and 5 .4% of the mutant chromosomes, respectively. Thirteen mutations had re lative frequencies of 1%-5%, and 55 mutations each had frequencies les s than or equal to 1%. The mutational spectrum corresponded to that ob served for the European ancestry of the U.S. population. To evaluate t he extent of allelic variation at the PAH locus within the United Stat es in comparison with other populations, we used allele frequencies to calculate the homozygosity for 11 populations where >90% ascertainmen t of mutations has been obtained. The United States was shown to conta in one of the most heterogeneous populations, with homozygosity values similar to Sicily and ethnically mixed sample populations in Europe. The extent of allelic heterogeneity must be a major determining factor in the choice of mutation-detection methodology for molecular diagnos is in PAH deficiency.