Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency

Abstract

Mutations in the phenylalanine hydroxylase (PAH) gene result in phenylketonuria (PKU). Tetrahydrobiopterin (BH4)-responsive hyperphenylalaninemia has been recently described as a variant of PAH deficiency caused by specific mutations in the PAH gene. It has been suggested that BH4-responsiveness may be predicted from the corresponding genotypes. Data from BH4 loading tests indicated an incidence of BH4-responsiveness of 440% in the general PKU population and 480% in mild PKU patients. The current project entailed genotype analysis of 315 BH4-responsive patients tabulated in the BIOPKUdb database and comparison with the data from the PAHdb locus-specific knowledgebase, as well as with previously published PAH mutations for several European countries, Northern China, and South Korea. We identified 57 mutations, presenting with a substantial residual PAH activity (average ~47%), presumed to be associated with BH4-responsiveness. More than 89% of patients are found to be compound heterozygotes. The three most common mutations found in 45% of BH4-responsive patients are p.A403 V, p.R261Q, and p.Y414C. Using the Hardy-Weinberg formula the predicted average frequency of BH4-responsiveness in European populations was calculated to be 55% (range 17–79%, lowest in Baltic countries and Poland and highest in Spain), 57% in Northern China, and 55% for South Korea. The genotype-predicted prevalence of BH4-responsiveness was higher than prevalence data obtained from BH4 loading tests. Inconsistent results were observed for mutations p.L48S, p.I65 T, p.R158Q, p.R261Q, and p.Y414C. Our data suggest that BH4-responsiveness may be more common than assumed and to some extent may be predicted or excluded from the patient’s genotype.