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The carrier rate of the phenylalanine hydoxylase gene (PAH) mutations p.Arg408Trp, pArg261Gln, and p.Arg261X in the populations of Eurasia

  • Medical Genetics
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Abstract

Analysis of the carrier frequency of p.Arg408Trp, p.Arg261Gln, and p.Arg261X mutations in the PAH gene was carried out in different unrelated indigenous individuals representing 58 populations of Eurasia taking into account their linguistic identity and territorial location. Mutation p.Arg408Trp in the PAH gene was found in 14 studied populations with the highest average carrier frequency of 0.0127 in the Volga-Ural region and 0.0134 in the representatives of the Slavic language group. Mutation p.Arg261Gln in the PAH gene was detected only in two populations with average carrier frequency rate of 0.0012 in the Volga-Ural region. Mutation p.Arg261X in the PAH gene was identified in four North Caucasus populations with highest carrier frequency in Karachays—at 0.0526. All PAH gene mutations in populations of Eurasia were identified in the heterozygous state.

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References

  1. Trunzo, R., Santacroce, R., D’Andrea, G., et al., Mutation analysis in hyperphenylalaninemia patients from South Italy, Clin. Biochem., 2013, vol. 46, pp. 1896–1898. doi 10.1016/j.clinbiochem.2013.06.009

    Article  CAS  PubMed  Google Scholar 

  2. Pangkanon, S., Ratrisawadi, V., Charoensiriwatana, W., et al., Phenylketonuria detected by the neonatal screening program in Thailand, Southeast Asian J. Trop. Med. Public Health, 2003, vol. 34, no. 3, pp. 179–181.

    PubMed  Google Scholar 

  3. Mitchell, J., Trakadis, Y., and Scriver, C., Phenylalanine hydroxylase deficiency, Genet. Med., 2011, vol. 13, pp. 697–707. doi 10.1097/GIM.0b013e3182141b48

    Article  CAS  PubMed  Google Scholar 

  4. Novikov, P.V., Hereditary pathology in the structure of childhood diseases and the organization of medical and genetic care for children in the Russian Federation, Med. Genet., 2008, vol. 7, no. 12, pp. 3–7.

    Google Scholar 

  5. Eisensmith, R., Okano, Y., Dasovich, M., et al., Multiple origins for phenyketonuria in Europe, Am. J. Hum. Genet., 1992, vol. 51, no. 6, pp. 1355—1365.

  6. Krawczak, M. and Zschocke, J., A role for overdominant selection in phenyketonuria? Evidence from molecular data, Hum. Mutat., 2003, vol. 21, pp. 394–397. doi 10.1002/humu.10205

    Article  CAS  PubMed  Google Scholar 

  7. http://www.biopku.org/pah/.

  8. Zschocke, J., Phenylketonuria mutations in Europe, Hum. Mutat., 2003, vol. 21, pp. 345–356. doi 10.1002/humu.10192

    Article  CAS  PubMed  Google Scholar 

  9. Li, N., Jia, H., Liu, Z., et al., Molecular characterization of phenylketonuria in a Chinese mainland population sing next-generation sequencing, Sci. Rep., 2015, vol. 5, p. 15769. doi 10.1038/srep15769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Akhmetova, V.L., Orazgalieva, M.G., Bermisheva, M.A., et al., Analysis of the PAH gene in patients with phenylketonuria from the republics of Bashkortostan, Kazakhstan and the North Caucasus, Matererily VIs”ezda Rossiiskogo obshchestva meditsinskikh genetikov (Proceedings of 6th Conference of Russian Society of Medical Genetisists), Rostov-on-Don, 2010, p. 14.

    Google Scholar 

  11. Khidiyatova, I.M., Akhmetova, V.L., Khusainova, R.I., et al., The population study of structural features of hereditary diseases genes in the Republic of Bashkortstan, Med. Genet., 2011, vol. 10, no. 6, pp. 13–24.

    Google Scholar 

  12. Akhmetova, V.L., Murzabaeva, S.Sh., and Khusnutdinova, E.K., Analysis of structural features of genes of monogenic hereditary diseases: phenylketonuria, Etnogenomika narodov Tsentral’noi Evrazii: struktura genofonda i molekulyarno-geneticheskie osnovy nasledstvennoi patologii (Etnogenomics of the Peoples of Central Eurasia: the Structure of the Gene Pool and the Molecular-Genetic Basis of Hereditary Pathology), Khusnutdinova, E.K., Ed., Ufa: Gilem, 2014, pp. 55–75.

  13. Orazgalieva, M.G., Svyatova, G.S., Akhmetova, V.L., and Khusnutdinova, E.K., Study of mutations of the phenylalanine hydroxylase gene among patients with phenylketonuria living in Kazakhstan, Med. Genet., 2005, no. 8, pp. 383–86.

    Google Scholar 

  14. Anichkina, A.A., Gavrilyuk, A.P., Tverskaya SM., and Polyakov, A.V., Analysis of the most common mutations in the PAH gene in patients with phenylketonuria, Med. Genet., 2003, vol. 2, no. 4, pp. 175–181.

    CAS  Google Scholar 

  15. Amelina, S.S., Kriventsova, N.V., Polyakov, A.V., and Zinchenko, R.A., Molecular and genetic typing of patients with phenylketonuria in Rostov Oblast, Med. Genet., 2004, vol. 3, no. 2, pp. 139–144.

    Google Scholar 

  16. Stepanova, A.A., The study of molecular-genetic nature of phenylketonuria in the Russian patient samples, Cand. Sci. (Med.) Dissertation, Moscow: Medical Genetics Research Center Russian Academy of Medical Sciences, 2005.

    Google Scholar 

  17. Baturina, O.A., Brenner, E.V., Tupikin, A.E., and Morozov, I.V., Molecular genetic study of the phenylalanine hydroxylase gene in patients with phenylketonuria in Western Siberia and the Far East, Med. Genet., 2009, vol. 9, no. 4, pp. 21–24.

    Google Scholar 

  18. Brenner, E.V., Molecular epidemiology and modern methods of gen diagnosis of phenylketonuria in the regions of Russia, Extended Abstract of Cand. Sci. (Biol.) Dissertation, Koltsovo: Vektor, 2009.

    Google Scholar 

  19. Matulevich, S.A., Mass screening of newborns for hereditary metabolic diseases as a part of the of medical and genetic care system for the population, Extended Abstract of Doctoral (Med.) Dissertation, Moscow: Med. Genet. Sci. Center, Russ. Acad. Med. Sci., 2009..

  20. Tsukerman, G., Gusina, N., et al., Population control of genetic diseases in Belarus: status and development, Brazil. J. Genet., 1996, vol. 19, no. 2, pp. 75–77.

    Google Scholar 

  21. Mathew, C.C., The isolation of high molecular weight eukaryotic DNA, Methods Mol. Biol., 1984, no. 2, pp. 31–34.

    CAS  Google Scholar 

  22. DiLella, A., Marvit, J., Brayton, K., et al., An aminoacid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2, Nature, 1987, vol. 327, pp. 333–336.

    Article  CAS  PubMed  Google Scholar 

  23. Kayaalp, E., Treacy, E., Waters, P., et al., Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a metanalysis of genotype—phenotype correlations, Am. J. Hum. Genet., 1997, vol. 61, pp. 1309–1317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bik-Multanowski, M., Kaluzny, L., Mozrzymas, R., et al., Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness, Acta Biochim. Pol., 2013, vol. 60, no. 4, pp. 613–616.

    PubMed  Google Scholar 

  25. Guldberg, F., Henriksen, K., Sipila, I., et al., Phenylketonuria in a low incidence population: molecular characterization of mutations in Finland, J. Med. Genet., 1995, vol. 32, pp. 976–978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zschocke, J., Mallory, J., Eiken, H., and Nevin, N., Phenylketonuria and the peoples of Northern Ireland, Hum. Genet., 1997, vol. 100, no. 2, pp. 189–194.

    Article  CAS  PubMed  Google Scholar 

  27. Sterl, E., Paul, K., Paschke, E., et al., Prevalence of tetrahydrobiopterin (BH4)-responsive alleles among Austrian patients with PAH deficiency: comprehensive results from molecular analysis in 147 patients, J. Inherit. Metab. Dis., 2013, vol. 36, pp. 7–13. doi 10.1007/s10545-012-9485-y

    Article  CAS  PubMed  Google Scholar 

  28. Groselj, U., Tansek, M., Kovac, J., et al., Five novel mutations and two large deletions in a population analysis of the phenylalanine hydroxylase gene, Mol. Genet. Metab., 2012, vol. 106, pp. 142–148. doi 10.1016/j.ymgme.2012.03.015

    Article  CAS  PubMed  Google Scholar 

  29. da Silva, L., Carvalho, T., da Silva, F., et al., Molecular characterization of phenylketonuria in South Brazil, Mol. Genet. Metab., 2003, vol. 79, pp. 17–24. http://dx.doi.org/. doi 10.1016/S1096-7192(03)00032-5

    Article  PubMed  Google Scholar 

  30. Carter, K., Byck, S., Waters, P., et al., Mutation at the phenylalanine hydroxylase gene (PAH) and its use to document population genetic variation: the Quebec experience, Eur. J. Hum. Genet., 1998, vol. 6, pp. 61–70.

    Article  CAS  PubMed  Google Scholar 

  31. Ho, G., Alexander, I., Bhattacharya, K., et al., The molecular bases of phenylketonuria (PKU) in New South Wales, Australia: mutation profile and correlation with tetrahydrobiopterin (BH4) responsiveness, JIMD Rep., 2014, vol. 14, pp. 55–65. doi 10.1007/8904_2013_284

    PubMed  Google Scholar 

  32. Guldberg, P., Levy, H., Hanley, W.B., et al., Phenylalanine Hydroxylase Gene Mutations in the United States: Report from the Maternal PKU Collaborative Study, Am. J. Hum. Genet., 1996, vol. 59, pp. 84–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Bercovich, D., Elimelech, A., Yardeni, T., et al., A mutation analysis of the phenylalanine hydroxylase (PAH) gene in the Israeli population, Ann. Hum. Genet., 2008, vol. 72, pp. 305–309. doi 10.1111/j.1469-1809.2007.00425.x

    Article  CAS  PubMed  Google Scholar 

  34. Eisensmith, R., Goltsov, A., O’Neill, Ch., et al., Recurrence of the R408W mutation in the phenylalanine hydroxylase locus in Europeans, Am. J. Hum. Genet., 1995, vol. 56, pp. 278–286.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Tighe, O., Dunican, D., O’Neill, C., et al., Genetic diversity within the R408W phenylketonuria mutation lineages in Europe, Hum. Mutat., 2003, vol. 4, pp. 387–393. doi 10.1002/humu.10195

    Article  Google Scholar 

  36. Zinchenko, R.A., El’chinova, G.I., Galkina, V.A., et al., Differentiation of ethnic groups in Russia by genes of hereditary diseases, Med. Genet., 2007, vol. 6, no. 2, pp. 29–37.

    Google Scholar 

  37. Ginter, E.K. and Zinchenko, R.A., Hereditary diseases in Russian populations, Inf. Vestn. Vavilovskogo O-va Genet. Sel., 2006, vol. 10, no. 1, pp. 106–125.

    Google Scholar 

  38. Bagheri, M., Rad, I.A., Jazani, N.H., et al., Mutation analysis of the phenylalanine hydroxylase gene in Azerbaijani population, a report from West Azerbaijan province of Iran, Iran J. Basic Med. Sci., 2015, vol. 18, no. 7, pp. 649–653.

    PubMed  PubMed Central  Google Scholar 

  39. Karam, P.E., Alhamra, R.S., Nemer, G., and Usta, J., Spectrum of mutations in Lebanese patients with phenylalanine hydroxylase deficiency, Gene, 2013, vol. 515, pp. 117–122. doi 10.1016/j.gene.2012.11.018

    Article  CAS  PubMed  Google Scholar 

  40. Murad, H., Dabboul, A., Moassas, F., et al., Mutation spectrum of phenylketonuria in Syrian population: genotype— phenotype correlation, Gene, 2013, vol. 528, pp. 241–247. doi 10.1016/j.gene.2013.07.001

    Article  CAS  PubMed  Google Scholar 

  41. Santos, L.L., Castro-Magalhaes, M., Fonseca, C.G., et al., PKU in Minas Gerais State, Brazil: mutation analysis, Ann. Hum. Genet., 2008, vol. 72, pp. 774–779. doi 10.1111/j.1469-1809.2008.00476.x

    CAS  PubMed  Google Scholar 

  42. Desviat, L.R., Pérez, B., Gutierrez, E., et al., Molecular basis of phenylketonuria in Cuba, Hum. Mutat., 2001, vol. 18, no. 3, p. 252. doi 10.1002/humu.1183

    Article  CAS  PubMed  Google Scholar 

  43. Effat, L., Kuzmin, A., Kasem, N., et al., Haplotypes and mutations of the PAH locus in Egyptian families with PKU, Eur. J. Hum. Genet., 1999, vol. 7, pp. 259–262.

    Article  CAS  PubMed  Google Scholar 

  44. Bashyam, M.D., Chaudhary, A.K., Kiran, M., et al., Splice, insertion-deletion and nonsense mutations that perturb the phenylalanine hydroxylase transcript cause phenylketonuria in India, J. Cell. Biochem., 2014, vol. 115, pp. 566–574. doi 10.1002/jcb.24692

    CAS  Google Scholar 

  45. Alibakhshi, R., Moradi, K., Mohebbi, Z., and Ghadiri, K., Mutation analysis of PAH gene in patients with PKU in western Iran and its association with polymorphisms: identification of four novel mutations, Metab. Brain Dis., 2014, vol. 29, pp. 131–138. doi 10.1007/s11011-013-9432-0

    Article  CAS  PubMed  Google Scholar 

  46. Dworniczak, B.1., Kalaydjieva, L., Aulehla-Scholz, C., et al., Recurrent nonsense mutation in exon 7 of the phenylalanine hydroxylase gene, Hum. Genet., 1991, vol. 87, no. 6, pp. 731–733.

    Article  CAS  PubMed  Google Scholar 

  47. El’chinova, G.I., Ivanov, A.V., Revazova, Yu.A., et al., Ethnic marriage assortativeness and intensity of metisation of Karachays, Russ. J. Genet., 2015, vol. 51, no. 8, pp. 807–811.

    Article  Google Scholar 

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Authors and Affiliations

  1. Institute of Biochemistry and Genetics, Ufa Scientific Center, Russian Academy of Sciences, Ufa, 450054, Russia

    V. L. Akhmetova, R. I. Khusainova, S. S. Litvinov & E. K. Khusnutdinova

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  1. V. L. Akhmetova
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  2. R. I. Khusainova
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  3. S. S. Litvinov
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  4. E. K. Khusnutdinova
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Correspondence to V. L. Akhmetova.

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Original Russian Text © V.L. Akhmetova, R.I. Khusainova, S.S. Litvinov, E.K. Khusnutdinova, 2017, published in Genetika, 2017, Vol. 53, No. 8, pp. 960–973.

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Akhmetova, V.L., Khusainova, R.I., Litvinov, S.S. et al. The carrier rate of the phenylalanine hydoxylase gene (PAH) mutations p.Arg408Trp, pArg261Gln, and p.Arg261X in the populations of Eurasia. Russ J Genet 53, 910–922 (2017). https://doi.org/10.1134/S1022795417060023

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