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Mutation analysis of the PAH gene in Ukrainian population, a report from west Ukraine region

Makukh H.V., Chorna L.B., Tyrkus M.Ya., Akopyan H.R., Shuvarska V.I., Malakhova A.Y., Poliakova Ye.O.


SUMMARY. Phenylketonuria (PKU) is one of the most common autosomal recessive diseases caused by inherited defect in phenylalanine hydroxylase (PAH) that impairs po-stnatal cognitive development. Mutations in the PAH gene lead to complete or partial loss of PAH enzyme activity which cause to increasing phenylalanine se-rum level and phenotypic manifestations of PKU. In order to determine the PAH mutations spectrum in the population from the West region of Ukraine, 158 unrelated PKU patients were studied. 101 patients with hyperphenylalaninemia (HPA) were selected during the neonatal screening program. DNA from peripheral blood leukocytes was isolated and purified using a modified salting out method. A total of 316 alleles were studied by means of restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR, ACRS-PCR) method. The most prevalent mutation was R408W, occurring in 58.54 % of all alleles, with a very high degree of homozygosity (35.44 %). The frequencies of remaining identified mutations were: IVS10nt-11G>A (4.35 %), R158Q (4.17 %), Y414C (2.78 %) and R252W (1.25 %). The most common mutation in patients with PKU from the West region of Ukraine is R408W. The spectrum and frequency of mutations are correlated with the frequency in the general population of Ukraine and corresponded to the mutation spectrum in Eastern Europe.

Key words: hyperphenylalaninemia, mutation, phenylalanine hydroxylase gene (PAH), phenylketonuria

Tsitologiya i Genetika 2021, vol. 55, no. 5, pp. 13-19

  • State Institution Institute of Hereditary Pathology of National Academy of Medical Sciences of Ukraine, 31-a, M. Lysenko Str., Lviv, Ukraine, 79008

E-mail: makukh.h

Makukh H.V., Chorna L.B., Tyrkus M.Ya., Akopyan H.R., Shuvarska V.I., Malakhova A.Y., Poliakova Ye.O. Mutation analysis of the PAH gene in Ukrainian population, a report from west Ukraine region, Tsitol Genet., 2021, vol. 55, no. 5, pp. 13-19.

In "Cytology and Genetics":
H. V. Makukh, L. B. Chorna, M. Ya. Tyrkus, H. R. Akopyan, V. I. Shuvarska, A. Y. Malakhova & Ye. O. Poliakova Analysis of the PAH Gene Mutations in the Ukrainian Population: A Report from the West Ukrainian Region, Cytol Genet., 2021, vol. 55, no. 5, pp. 414419
DOI: 10.3103/S0095452721050066


1. Blau, N., Shen, N., and Carducci, C., Molecular genetics and diagnosis of phenylketonuria: state of the art, Expert Rev. Mol. Diagn., 2014, vol. 6, pp. 655671.

2. DiLella, A.G., Marvit, J., Brayton, K., et al., An amino-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2, Nature, 1987, vol. 327, pp. 333338.

3. Eiken, H.G., Odland, E., Boman, H., et al., Application of natural and amplification created restriction sites for the diagnosis of PKU mutations, Nucleic Acids Res., 1991, vol. 19, pp. 14271430.

4. Erlandsen, H. and Stevens, R.C., The structural basis of Phenylketonuria, Mol. Genet. Metab., 1999, vol. 68, pp. 103125.

5. Guldberg, P., Rey, F., Zschocke, J., et al., A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype, Am. J. Hum. Genet., 1998, vol. 63, pp. 7179. doi 10.1086/301920

6. Hoang, L., Byck, S., Prevost, et al., PAH mutation analysis Consortium Database: a database for disease-producing and other allelic variation at the human PAH locus, Nucleic Acids Res., 1999, vol. 24, no. 1, pp. 127131.

7. Kaufman, S., Berlow, S., Summer, G.K., et al., Hyperphenylalaninemia due to a deficiency of biopterin. A variant form of Phenylketonuria, N. Engl. J. Med., 1978, vol. 299, no. 13, pp. 673679. 2991301

8. Kayaalp, E., Treacy, E., Waters, P.J., et al., Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a metanalysis of genotype-phenotype correlations, Am. J. Hum. Genet., 1997, vol. 61, pp. 13091317.

9. Longo, N., Arnold, G.L., Pridjian, G., et al., Long-term safety and efficacy of sapropterin: the PKUDOS registry experience, Mol. Genet. Metab., 2015, vol. 114, pp. 557563.

10. Okano, Y., Eisensmith, R.C., Güttler, F., et al., Molecular basis of phenotypic heterogeneity in Phenylketonuria, N. Eng. J. Med., 1991, vol. 324, pp. 12321238.

11. ONeill, C.A., Eisensmith, R.C., Croke, D.T., et al., Molecular analysis of PKU in Ireland, Acta Paediatr. Suppl., 1994, vol. 407, pp. 4344. 13448.x

12. Pampukha, V., Nechyporenko, M., and Livshyts, L., Ana-lysis of EX5del4232ins268 and EX5del955 PAH gene mutations in Ukrainian patients with Phenylketonuria, Genes Dis., 2017, vol. 4, no. 2, pp. 108110.

13. Pey, A.L., Stricher, F., Serrano, L., et al., Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases, Am. J. Hum. Genet., 2007, vol. 81, pp. 10061024.

14. Réblová, Kl., Hrubá, Z., Procházková, D., et al., Hyperphenylalaninemia in the Czech Republic: genotype-phenotype correlations and in silico analysis of novel missense mutations, Clin. Chim. Acta, 2013, vol. 419, pp. 110.

15. Scriver, C.R., The PAH gene, phenylketonuria, and a paradigm shift, Hum. Mutat., 2007, vol. 28, no. 9, pp. 831845.

16. Scriver, C.R. and Kaufman, S., Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. The metabolic and molecular bases of inherited disease, OMMBID, 2001, vol. 8, pp. 16671724.

17. Singh, R.H., Rohr, F., Frazier, D., et al., Recommendations for the nutrition management of phenylalanine hydroxylase deficiency, Genet. Med., 2014, vol. 16, no. 2, pp. 121131.

18. Tighe, O., Dunican, D., ONeill, C., et al., Genetic diversity within the R408W phenylketonuria mutation lineages in Europe, Hum. Mutat., 2003, vol. 21, pp. 387393.

19. Van Spronsen, F.J., van Wegberg, A.M.J., Ahring, K., et al., Key European guidelines for the diagnosis and management of patients with phenylketonuria, Lancet Diabetes Endocrinol., 2017, vol. 5, no. 9, pp. 743756.

20. Van Wegberg, A.M.J., MacDonald, A., Ahring, K., et al., The complete European guidelines on phenylketonuria: diagnosis and treatment, Orphanet J. Rare Dis., 2017, vol. 12, no. 1, p. 162.

21. Vockley, J., Anderson, H.C., Antshel, K.M., et al., Phenylalanine hydroxylase deficiency: diagnosis and management guideline, Genet. Med., 2014, vol. 16, pp. 188200.

22. Woo, S.L., Lidsky, A.S., Guttler, F., et al., Cloned human phenylalanine hydroxylase gene allows prenatal diagnosis and carrier detection of classical phenylketonuria, Nature, 1983, vol. 306, pp. 151155.

23. Zekanowski, C., Nowacka, M., Zgulska, M., et al., Frequencies of the most common mutations responsible for phenylketonuria in Poland, Mol. Cell Probes, 1994, vol. 8, pp. 323324.

24. Zschocke, J., Graham, C.A., Carson, D.J., and Nevin, N.C., Phenylketonuria mutation analysis in Northern Ireland: a rapid stepwise approach, Am. J. Hum. Genet., 1995, vol. 57, pp. 13111317.

25. Zschocke, J., Phenylketonuria mutations in Europe, Hum. Mutat., 2003, vol. 21, no. 4, pp. 345356.

26. Zurflüh, M.R., Zschocke, J., Lindner, M., et al., Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency, Hum. Mutat., 2008, vol. 29, no. 1, pp. 167175.

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