Phenylketonuria mutations in Europe

Abstract

For the PKU Special IssuePhenylketonuria (PKU) is heterogeneous. More than 400 different mutations in the phenylalanine hydroxylase (PAH) gene have been identified. In a systematic review of the molecular genetics of PKU in Europe we identified 29 mutations that may be regarded as prevalent in European populations.Comprehensive regional data for these mutations were collated from all available studies. The spectrum of mutations found in individual regions results from a combination of factors including founder effect, range expansion and migration, genetic drift, and probably heterozygote advantage.

The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness

“…Allele frequencies are calculated using total number of chromosomes tested more common in VIC than in NSW (Ramus et al 1995), but otherwise the distribution of mutations in the two populations was similar. The p.R408W mutation was the predominant mutation in Ireland, Latvia and Lithuania (O'Donnell et al 2002;Kasnauskiene et al 2003;Pronina et al 2003), whereas c.1315+1G>A had the highest frequency in England, Germany and Denmark (Guldberg et al 1993;Aulehla-Scholz and Heilbronner 2003;Zschocke 2003). Other examples of region-specific mutations include c.1066-11G>A from Mediterranean regions and p.R243Q and p.R413P from Asia (Chien et al 2004;Lee et al 2004;Song et al 2005).…”

“…However, the pathogenic mutations in New South Wales have not been previously studied. Phenotype-genotype correlations in PKU have shown clear associations between some mutations and the severity of disease (Kayaalp et al 1997;Bénit et al 1999;G€ uttler et al 1999;Zschocke 2003;Bercovich et al 2008). Due to the large number of mutations and the low population frequency of some of these mutations, it is often difficult to ascertain the phenotypic consequences of a given mutation and correlations may also give rise to conflicting results (Bercovich et al 2008).…”

Molecular Genetics and Genotype-Based Estimation of BH4-Responsiveness in Serbian PKU Patients: Spotlight on Phenotypic Implications of p.L48S

“…Mutations p.P281L and p.E390G are relatively common in Balkans, but rare in other European populations. Thus, p.P281L was found on 10% alleles in Greece, 8.4% in Turkey, 8% in Croatia, and 6% in Serbia, while p.E390G accounted for 7% of alleles in Croatia, 5.2% in Serbia, and 4.1% in Turkey (Zschocke 2003;Karacic et al 2009;Dobrowolski et al 2011). Although mentioned frequencies are quite similar, we could observe gradient from southeast to northwest for p.P281L and the inverse for p.E390G.…”

“…It is the most prevalent mutation worldwide, which is associated with two different haplotypes and in Slavic populations it follows the cline distribution from Baltic to Mediterranean countries (Zschocke 2003). Since its frequency is 84% in Estonia, 46% in Slovakia, and 36% in Croatia, detected frequency in Serbia (16.4%) fits into the established gradient distribution.…”

“…This mutation was initially detected in a Turkish patient with phenylketonuria (Konecki et al 1991). Since then it has been identified in many European populations usually with a frequency of 2-5% (Zschocke 2003). Higher frequencies have been found in Croatian (10%), Italian (9.7%), and Turkish (7%) populations which are geographically and historically interconnected with the Serbian population (Giannattasio et al 2001;Karacic et al 2009;Dobrowolski et al 2011).…”