Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency

Abstract

Mutations in the phenylalanine hydroxylase (PAH) gene result in phenylketonuria (PKU). Tetrahydrobiopterin (BH(4))-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 BH(4)-responsiveness may be predicted from the corresponding genotypes. Data from BH(4) loading tests indicated an incidence of BH(4)-responsiveness of >40% in the general PKU population and >80% in mild PKU patients. The current project entailed genotype analysis of 315 BH(4)-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 approximately 47%), presumed to be associated with BH(4)-responsiveness. More than 89% of patients are found to be compound heterozygotes. The three most common mutations found in >5% of BH(4)-responsive patients are p.A403 V, p.R261Q, and p.Y414C. Using the Hardy-Weinberg formula the predicted average frequency of BH(4)-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 BH(4)-responsiveness was higher than prevalence data obtained from BH(4) loading tests. Inconsistent results were observed for mutations p.L48S, p.I65 T, p.R158Q, p.R261Q, and p.Y414C. Our data suggest that BH(4)-responsiveness may be more common than assumed and to some extent may be predicted or excluded from the patient's genotype.

Mutational spectrum of phenylketonuria in Jiangsu province

“…Several studies have investigated the correlation between patients' genotypes and their response to drug treatment; they suggest that genotype plays an important role in BH4 responsiveness [8,14,21]. The current study predicted BH4 responsiveness among individuals with at least one mutation expressing substantial residual activity in vitro (>10 %).…”

“…The identification of the c.722G>A locus was first reported in 1993, when Guldberg et al assessed the mutational spectrum of PKU in southern Europe (i.e., Sicily) [6]. In 2008, Zurflüh et al studied the function of PAH and found that the c.722G>A alteration reduced the activity of PAH to 23 % prior to mutation; these authors also demonstrated that the mutated locus affected the catalytic activity of the enzyme domain of PAH, thereby leading to the reduction of enzyme activity [21]. Zschocke et al reported the c.1194A>G locus, which was identified through the study of 546 independent alleles in Germany.…”

Significance of genotype in tetrahydrobiopterin‐responsive phenylketonuria

“…The reasons for this may be multifactorial. As shown for the mutation p.R158Q, this may simply be due to definition, as pointed out by Zurflü h et al (2008). In patients compound heterozygous for two responsive mutations and without effect on Phe level after BH 4 loading, a negative inter-allelic complementation may exist.…”

Tetrahydrobiopterin responsiveness after extended loading test of 12 Danish PKU patients with the Y414C mutation

“…Originally, it was thought that, primarily, mutations located at the catalytic domain binding site for BH4 in PAH were responsive to BH4 (Erlandsen and Stevens 2001). However, the growing list of responsive mutations reveals mutations from all the domains of PAH (Matalon et al 2004;Zurflüh et al 2008). It has been suggested that some chaperone-like effect of BH4 on enzyme stability is involved (Pey et al 2004).…”