Skip to main content

The study of the full spectrum of variants leading to hyperphenylalaninemia have revealed 10 new variants in the PAH gene

Abstract

This study presents further research into the spectrum of variants in genes responsible for the development of phenylketonuria (PKU) and hyperphenylalaninemia (HPA) in patients in Russia. After a study of 25 frequent variants, 293 patients (327 chromosomes without detected variants) from among 1265 probands still had no confirmed diagnosis. A study involving methods of next generation sequencing (NGS) of PAH, PTS, GCH1, PCBD1, QDPR, SPR and DNAJC12 genes to search for point mutations and multiplex ligation-dependent probe amplification (MLPA) methods to search for gross deletions were conducted for these patients. Among 327 chromosomes without identified variants, variants in the PAH gene were found on 260 chromosomes, and variants in the PTS gene were found on 10 chromosomes. On 10 chromosomes gross deletions by the MLPA method were detected. 104 rare variants of the РАН gene, including 10 variants not previously described, and 6 variants of the PTS gene were revealed. The NGS method revealed additional РАН gene variants on 10.3% of chromosomes and PTS gene variants on 0.4%. Gross deletions of the РАН gene were revealed in 0.5% of chromosomes. Thus, the most complete understanding of the spectrum of variants leading to the development of the PKU and HPA in Russia with the use of all methods available today has been obtained. Such a detailed study of the spectrum of rare variants on the genetic material from Russia was undertaken for the first time.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. Anikster Y, Haack TB, Vilboux T, Pode-Shakked B, Thöny B, Shen N, Guarani V, Meissner T, Mayatepek E, Trefz FK, Marek-Yagel D, Martinez A, Huttlin EL, Paulo JA, Berutti R, Benoist JF, Imbard A, Dorboz I, Heimer G, Landau Y, Ziv-Strasser L, Malicdan MCV, Gemperle-Britschgi C, Cremer K, Engels H, Meili D, Keller I, Bruggmann R, Strom TM, Meitinger T, Mullikin JC, Schwartz G, Ben-Zeev B, Gahl WA, Harper JW, Blau N, Hoffmann GF, Prokisch H, Opladen T, Schiff M (2017) Biallelic mutations in DNAJC12 cause Hyperphenylalaninemia, dystonia, and intellectual disability. Am J Hum Genet 100:257–266. https://doi.org/10.1016/j.ajhg.2017.01.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. BIOPKU (2006-2019) http://www.biopku.org

  3. Birk Moller L et al (2007) Low proportion of whole exon deletions causing phenylketonuria in Denmark and Germany. Hum Mutat 28:207. https://doi.org/10.1002/humu.9481

    Article  PubMed  Google Scholar 

  4. Blau N (2016) Genetics of phenylketonuria: then and now. Hum Mutat 37:508–515. https://doi.org/10.1002/humu.22980

    CAS  Article  PubMed  Google Scholar 

  5. Bonafe L, Thony B, Penzien JM, Czarnecki B, Blau N (2001) Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia. Am J Hum Genet 69:269–277. https://doi.org/10.1086/321970

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Chiu YH, Chang YC, Chang YH, Niu DM, Yang YL, Ye J, Jiang J, Okano Y, Lee DH, Pangkanon S, Kuptanon C, Hock NL, Chiong MA, Cavan BV, Hsiao KJ, Liu TT (2012) Mutation spectrum of and founder effects affecting the PTS gene in east Asian populations. J Hum Genet 57:145–152. https://doi.org/10.1038/jhg.2011.146

    CAS  Article  PubMed  Google Scholar 

  7. Dhondt JL, Farriaux JP, Boudha A, Largilliere C, Ringel J, Roger MM, Leeming RJ (1985) Neonatal hyperphenylalaninemia presumably caused by guanosine triphosphate-cyclohydrolase deficiency. J Pediatr 106:954–956

    CAS  Article  Google Scholar 

  8. Dudesek A, Roschinger W, Muntau AC, Seidel J, Leupold D, Thony B, Blau N (2001) Molecular analysis and long-term follow-up of patients with different forms of 6-pyruvoyl-tetrahydropterin synthase deficiency. Eur J Pediatr 160:267–276

    CAS  Article  Google Scholar 

  9. Grobe H, Bartholome K, Milstien S, Kaufman S (1978) Hyperphenylalaninaemia due to dihydropteridine reductase deficiency. Eur J Pediatr 129:93–98

    CAS  Article  Google Scholar 

  10. Gundorova P, Stepanova AA, Kuznetsova IA, Kutsev SI, Polyakov AV (2019) Genotypes of 2579 patients with phenylketonuria reveal a high rate of BH4 non-responders in Russia. PLoS One 14:e0211048. https://doi.org/10.1371/journal.pone.0211048

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Jeannesson-Thivisol E, Feillet F, Chéry C, Perrin P, Battaglia-Hsu SF, Herbeth B, Cano A, Barth M, Fouilhoux A, Mention K, Labarthe F, Arnoux JB, Maillot F, Lenaerts C, Dumesnil C, Wagner K, Terral D, Broué P, de Parscau L, Gay C, Kuster A, Bédu A, Besson G, Lamireau D, Odent S, Masurel A, Guéant JL, Namour F (2015) Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness. Orphanet J Rare Dis 10:158. https://doi.org/10.1186/s13023-015-0375-x

    Article  PubMed  PubMed Central  Google Scholar 

  12. Li N, Jia H, Liu Z, Tao J, Chen S, Li X, Deng Y, Jin X, Song J, Zhang L, Liang Y, Wang W, Zhu J (2015) Molecular characterisation of phenylketonuria in a Chinese mainland population using next-generation sequencing. Sci Rep 5:15769. https://doi.org/10.1038/srep15769

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Richards S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424. https://doi.org/10.1038/gim.2015.30

    Article  PubMed  PubMed Central  Google Scholar 

  14. Stepanova AA, Polyakov AV, Tverskaya SM (2006) Molekulyarno-geneticheskoye issledovaniye genov tetrogidrobiopterinovogo obmena QDPR i PTS v gruppe rossiyskikh bol'nykh fenilketonuriyey [in russ]. Med Genet 9:3–8

  15. Thony B et al (1998) Hyperphenylalaninemia with high levels of 7-biopterin is associated with mutations in the PCBD gene encoding the bifunctional protein pterin-4a-carbinolamine dehydratase and transcriptional coactivator (DCoH). Am J Hum Genet 62:1302–1311. https://doi.org/10.1086/301887

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Trujillano D, Perez B, González J, Tornador C, Navarrete R, Escaramis G, Ossowski S, Armengol L, Cornejo V, Desviat LR, Ugarte M, Estivill X (2014) Accurate molecular diagnosis of phenylketonuria and tetrahydrobiopterin-deficient hyperphenylalaninemias using high-throughput targeted sequencing. Eur J Hum Genet 22:528–534. https://doi.org/10.1038/ejhg.2013.175

    CAS  Article  PubMed  Google Scholar 

  17. van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ (2017) The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis 12:162. https://doi.org/10.1186/s13023-017-0685-2

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wang R, Shen N, Ye J, Han L, Qiu W, Zhang H, Liang L, Sun Y, Fan Y, Wang L, Wang Y, Gong Z, Liu H, Wang J, Yan H, Blau N, Gu X, Yu Y (2018) Mutation spectrum of hyperphenylalaninemia candidate genes and the genotype-phenotype correlation in the Chinese population. Clin Chim Acta 481:132–138. https://doi.org/10.1016/j.cca.2018.02.035

    CAS  Article  PubMed  Google Scholar 

  19. Zekanowski C, Nowacka M, Sendecka E, Sowik M, Cabalska B, Bal J (1998) Identification of mutations causing 6-Pyruvoyl- tetrahydrobiopterin synthase deficiency in polish patients with variant Hyperphenylalaninemia. Mol Diagn 3:237–239 https://doi.org/10.1016/S1084-8592(98)80047-7

    CAS  Article  Google Scholar 

  20. Zurfluh MR et al (2008) Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Hum Mutat 29:167–175. https://doi.org/10.1002/humu.20637

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are grateful for the participation of all patients in this study. We would like to thank clinical genetic specialists from all over the country for their cooperation.

Funding

The research was carried out within the state assignment of Ministry of Science and Higher Education of the Russian Federation.

Author information

Affiliations

Authors

Corresponding author

Correspondence to I. Kuznetcova.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kuznetcova, I., Gundorova, P., Ryzhkova, O. et al. The study of the full spectrum of variants leading to hyperphenylalaninemia have revealed 10 new variants in the PAH gene. Metab Brain Dis 34, 1547–1555 (2019). https://doi.org/10.1007/s11011-019-00461-w

Download citation

Keywords

  • Next generation sequencing
  • Tetrahydrobiopterin
  • Phenylketonuria
  • Hyperphenylalaninemia