PAH and QDPR deficiency associated mutations in the Novosibirsk region of the Russian Federation: Correlation of mutation type with disease manifestation and severity

Abstract

Background: Efficient treatment of inherited hyperphenylalaninemia requires exact identification of mutations defining the trait. Such knowledge is important both for effective individual therapy and understanding of the genetic history and evolution of regional populations. Methods: DNA sequencing of amplified genome regions was used to identify mutations. Results: Hyperphenylalaninemia-associated mutations in the phenylalanine hydroxylase locus were identified for 76 unrelated patients from the Novosibirsk region, Russia and for their family members. Twenty-one mutation types were identified, most of them rare and one (IVS2 + 1delG) not previously described. Common for European populations, the mutation p.R408W appeared to be the most frequent, with allele frequency 63.33%. We also looked for mutations in the quinoid dihydropteridine reductase locus in some patients. For 36 unrelated children PKU patients with known blood phenylalanine levels, we tried to find correlations between this level and the genotype. Conclusions: Comparative analysis revealed correlations between blood phenylalanine levels and genotypes. The spectrum of phenylalanine hydroxylase mutations in the Novosibirsk region population appeared to be rather complex, probably as a result of mixed ethnic composition, formed by several multidirectional migration flows.

Keywords

• hyperphenylalaninemia
• phenylketonuria
• phenylalanine hydroxylase
• genotype
• phenotype