Hyperphenylalaninemia in the Czech Republic: Genotype–phenotype correlations and in silico analysis of novel missense mutations

Functional and structural characterisation of 5 missense mutations of the phenylalanine hydroxylase

“…We previously identified five PAH variants (p.F233I, p.R270I, p.F331S, p.S350Y, and p.L358F) in Slovak PKU patients with an unknown impact on the resultant protein (Polak et al 2013). The variants p.F233I, p.R270I, p.F331S, and p.S350Y were identified for the first time in the Slovak population while the p.L358F variant was identified in Czech PKU patients contemporaneously with our findings, and it was classified as a mild mutation by in silico analysis (Réblová et al 2013). In the positions F233, R270, F331, and S350, other amino acid substitutions ere also noted (Kleiman et al 1993;Benit et al 1994;Kuzmin et al 1995;Guldberg et al 1996Guldberg et al , 1998Tyfield et al 1997;Leuzzi et al 2006;Zhu et al 2010), but only two of them, p.R270S and p.R270K, were functionally assayed in vitro (Bjørgo et al 1998;Trunzo et al 2016).…”

“…The most frequent missense mutations were functionally and structurally characterised in several studies many years ago (Waters 2003). However, large-scale PKU studies continuously reveal novel variants with an unknown impact on PAH enzyme function (Groselj et al 2013;Polak et al 2013;Réblová et al 2013;Trunzo et al 2015). Therefore, it is highly important to constantly update and extend these data which contribute to a better understanding of the complex PKU nature.…”

Comparative Analysis of Phenylalanine Hydroxylase Mutations Spectrum in Novosibirsk and Kemerovo regions of Western Siberia, Russia

“…Homozygosity index for the cohort studied was 0.38 which is comparable with ethnically heterogenous Northern and Eastern Europe populations. For comparison we calculated homozygosity indexes from the literature data on mutations frequencies for some European countries: 0.58 for Latvia [6], 0.55 for Lithuania [7], 0.31 for Czech Republic [8], 0.38 for Poland [9], 0.38 for Iceland [10], 0.20 for Denmark [11]. On the contrary, calculated homozygosity indexes for more genetically homogenous Asian appeared to be much lower: 0.12 for Japan [12], 0.051 for Korea [13], 0.043 for China [14].…”

“…The PKU-associated mutations spectra in Novosibirsk and Kemerovo regions share several common features. In both regions p.R408W absolutely dominates like in many European populations (76.0% in Latvia [6], 66.6% in Ukraine [19], 55.0% in Poland [9], 42.1% in Czech [8]. The next common mutation p.R261Q (13 hemizygous cases in Novosibirsk region and 3 -in Kemerovo region) is known to be wide spread in Switzerland and North Italy [10], Portugal [20] and Turkey [21].…”

Genetics of Phenylketonuria: Then and Now

“…Since the genotype determines the activity of PAH and thus the metabolic phenotype, there is growing evidence of genotype–phenotype correlation [Trefz et al., ; Kayaalp et al., ; Benit et al., ; Jennings et al., ; Kasnauskiene et al., ; Pey et al., ; Bercovich et al., ; Daniele et al., ; Bueno et al., Polak et al., ; Reblova et al., ; Tao et al., ; Trunzo et al., ]. It has been known for about 20 years that PAH activity predicts the clinical phenotype (blood Phe) in PKU [Eisensmith and Woo, ].…”