COMPLEX F8 GENE REARRANGEMENTS

DOI: https://doi.org/10.29296/24999490-2019-01-07

T.S. Beskorovainaya(1), T.B. Milovidova(1), O.A. Shchagina(1), E.G. Matushchenko(1), M.S. Petuhova(1), O.K. Togochakova(2), V.V. Salomashkina(3), O.S. Pshenichnikova(3), V.L. Surin(3), A.V. Polyakov(1), E.K. Ginter(1) 1-Research Centre for Medical Genetics, Moskvorechie str., 1, Moscow, 115522, Russian Federation; 2-Khakassia Republican clinical perinatal center, Krylova str., 66/1, Abakan, 655003, Russian Federation; 3-National Medical Research center of Hematology, Novy Zykovsky pr., 4, Moscow, 125167, Russian Federation Е-mail: t-kovalevskaya@yandex.ru

Introduction. Hemophilia A is a frequent X-linked recessive disorder associated with the absence or functional defect of blood clotting factor VIII. Вoth point mutations and large structural rearrangements – deletions, duplications, and inversions were described in the F8 gene. Large structural abnormalities are detected in half of the patients with severe hemophilia А. The aim of the study. To characterize the F8 gene structural rearrangements casually detected during the study of the intron 1 and intron 22 inversions in hemophilia A patients from the Russian Federation. Methods. The study was carried out by standard PCR, IS-PCR and quantitative MLPA analysis. Results. Nine abnormal patterns were obtained in families with severe hemophilia A by standard PCR, IS-PCR and quantitative MLPA analysis during routine diagnostic detection of intron 1 and intron 22 inversions and large deletions/duplications in the F8 gene. It was due to unbalanced genomic rearrangements in these patients. Five large deletions and four large duplications were identified. Among them, there were four cases combined with intron 1 inversion and one with intron 22 inversion. Conclusion. At the moment, we can only hypothesize the sequence of events and the mechanism that led to the formation of these anomalies. All available molecular genetic methods should be used to detect and characterize complex rearrangements.
Keywords: 
Hemophilia A, F8, intron 1 inversion, intron 22 inversion, deletion, duplication

Список литературы: 
  1. Mannucci P.M., Tuddenham E.G. The hemophilias--from royal genes to gene therapy. N. Engl. J. Med. 2001; 344 (23): 1773–9. https://doi.org/10.1056/nejm200106073442307.
  2. Graw J., Brackmann H.H., Oldenburg J., Schneppenheim R., Spannagl M., Schwaab R. Haemophilia A: from mutation analysis to new therapies. Nat Rev Genet. 2005; 6 (6): 488–501. https://doi.org/10.1038/nrg1617.
  3. Schroder J., El-Maarri O., Schwaab R., Muller C.R., Oldenburg J. Factor VIII intron-1 inversion: frequency and inhibitor prevalence. J Thromb Haemost. 2006; 4 (5): 1141–3. https://doi.org/10.1111/j.1538-7836.2006.01884.x.
  4. Bagnall R.D., Waseem N., Green P.M., Giannelli F. Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A. Blood. 2002; 99 (1): 168–74.
  5. Gouw S.C., van den Berg H.M., Oldenburg J., Astermark J., de Groot P.G., Margaglione M., Thompson A.R., van Heerde W., Boekhorst J., Miller C.H., le Cessie S., van der Bom J.G. F8 gene mutation type and inhibitor development in patients with severe hemophilia A: systematic review and meta-analysis. Blood. 2012; 119 (12): 2922–34. https://doi.org/10.1182/blood-2011-09-379453.
  6. Gu W., Zhang F., Lupski J.R. Mechanisms for human genomic rearrangements. Pathogenetics. 2008; 1 (1): 4. https://doi.org/10.1186/1755-8417-1-4.
  7. Rossetti L.C., Radic C.P., Larripa I.B., De Brasi C.D. Genotyping the hemophilia inversion hotspot by use of inverse PCR. Clin Chem. 2005; 51 (7): 1154–8. https://doi.org/10.1373/clinchem.2004.046490.
  8. Rossetti L.C., Radic C.P., Larripa I.B., De Brasi C.D. Developing a new generation of tests for genotyping hemophilia-causative rearrangements involving int22h and int1h hotspots in the factor VIII gene. J Thromb Haemost. 2008; 6 (5): 830–6. https://doi.org/10.1111/j.1538-7836.2008.02926.x.
  9. Lupski J.R., Stankiewicz P. Genomic disorders: molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet. 2005; 1 (6): 49. https://doi.org/10.1371/journal.pgen.0010049.
  10. Turner D.J., Miretti M., Rajan D., Fiegler H., Carter N.P., Blayney M.L., Beck S., Hurles M.E. Germline rates of de novo meiotic deletions and duplications causing several genomic disorders. Nat Genet. 2008; 40 (1): 90–5. https://doi.org/10.1038/ng.2007.40.
  11. Shaw C.J., Lupski J.R. Implications of human genome architecture for rearrangement-based disorders: the genomic basis of disease. Hum Mol Genet. 2004; 13 (1): 57–64. https://doi.org/10.1093/hmg/ddh073.
  12. Bailey J.A., Eichler E.E. Primate segmental duplications: crucibles of evolution, diversity and disease. Nat Rev Genet. 2006; 7 (7): 552–64. https://doi.org/10.1038/nrg1895.
  13. Rossetti L.C., Goodeve A., Larripa I.B., De Brasi C.D. Homeologous recombination between AluSx-sequences as a cause of hemophilia. Hum Mutat. 2004; 24 (5): 440. https://doi.org/10.1002/humu.9288.
  14. Reiter L.T., Murakami T., Koeuth T., Pentao L., Muzny D.M., Gibbs R.A., Lupski J.R. A recombination hotspot responsible for two inherited peripheral neuropathies is located near a mariner transposon-like element. Nat Genet. 1996; 12 (3): 288–97. https://doi.org/10.1038/ng0396-288.
  15. Lopez-Correa C., Dorschner M., Brems H., Lazaro C., Clementi M., Upadhyaya M., Dooijes D., Moog U., Kehrer-Sawatzki H., Rutkowski J.L., Fryns J.P., Marynen P., Stephens K., Legius E. Recombination hotspot in NF1 microdeletion patients. Hum Mol Genet. 2001; 10 (13): 1387–92.
  16. Lupski J.R. Hotspots of homologous recombination in the human genome: not all homologous sequences are equal. Genome Biol. 2004; 5 (10): 242. https://doi.org/10.1186/gb-2004-5-10-242.
  17. Lakich D., Kazazian H.H., Jr., Antonarakis S.E., Gitschier J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat Genet. 1993; 5 (3): 236–41. https://doi.org/10.1038/ng1193-236.
  18. Naylor J.A., Buck D., Green P., Williamson H., Bentley D., Giannelli F. Investigation of the factor VIII intron 22 repeated region (int22h) and the associated inversion junctions. Hum Mol Genet. 1995; 4 (7): 1217–24.
  19. Abou-Elew H., Ahmed H., Raslan H., Abdelwahab M., Hammoud R., Mokhtar D., Arnaout H. Genotyping of intron 22-related rearrangements of F8 by inverse-shifting PCR in Egyptian hemophilia A patients. Ann Hematol. 2011; 90 (5): 579–84. https://doi.org/10.1007/s00277-010-1115-x.
  20. Lannoy N., Grisart B., Eeckhoudt S., Verellen-Dumoulin C., Lambert C., Vikkula M., Hermans C. Intron 22 homologous regions are implicated in exons 1–22 duplications of the F8 gene. Eur. J. Hum Genet. 2013; 21 (9): 970–6. https://doi.org/10.1038/ejhg.2012.275.
  21. Jourdy Y., Chatron N., Fretigny M., Carage M.L., Chambost H., Claeyssens-Donadel S., Roussel-Robert V., Negrier C., Sanlaville D., Vinciguerra C. Molecular cytogenetic characterization of five F8 complex rearrangements: utility for haemophilia A genetic counselling. Haemophilia. 2017; 23 (4): 316–23. https://doi.org/10.1111/hae.13218.
  22. Brinke A., Tagliavacca L., Naylor J., Green P., Giangrande P., Giannelli F. Two chimaeric transcription units result from an inversion breaking intron 1 of the factor VIII gene and a region reportedly affected by reciprocal translocations in T-cell leukaemia. Hum Mol. Genet. 1996; 5 (12): 1945–51.
  23. Weterings E., van Gent D.C. The mechanism of non-homologous end-joining: a synopsis of synapsis. DNA Repair (Amst). 2004; 3 (11): 1425–35. https://doi.org/10.1016/j.dnarep.2004.06.003.
  24. Lieber M.R. The mechanism of human nonhomologous DNA end joining. J. Biol. Chem. 2008; 283 (1): 1–5. https://doi.org/10.1074/jbc.R700039200.
  25. Toffolatti L., Cardazzo B., Nobile C., Danieli G.A., Gualandi F., Muntoni F., Abbs S., Zanetti P., Angelini C., Ferlini A., Fanin M., Patarnello T. Investigating the mechanism of chromosomal deletion: characterization of 39 deletion breakpoints in introns 47 and 48 of the human dystrophin gene. Genomics. 2002; 80 (5): 523–30.
  26. Oldenburg J., Pavlova A. Genetic risk factors for inhibitors to factors VIII and IX. Haemophilia. 2006; 12 (6): 15–22. https://doi.org/10.1111/j.1365-2516.2006.01361.x.
  27. Lee J.A., Carvalho C.M., Lupski J.R. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell. 2007; 131 (7): 1235–47. https://doi.org/10.1016/j.cell.2007.11.037.
  28. Hastings P.J., Lupski J.R., Rosenberg S.M., Ira G. Mechanisms of change in gene copy number. Nat Rev Genet. 2009; 10 (8): 551–64. https://doi.org/10.1038/nrg2593.
  29. Vanmarsenille L., Giannandrea M., Fieremans N., Verbeeck J., Belet S., Raynaud M., Vogels A., Mannik K., Ounap K., Jacqueline V., Briault S., Van Esch H., D’Adamo P., Froyen G. Increased dosage of RAB39B affects neuronal development and could explain the cognitive impairment in male patients with distal Xq28 copy number gains. Hum Mutat. 2014; 35 (3): 377–83. https://doi.org/10.1002/humu.22497.
  30. Janczar S., Fogtman A., Koblowska M., Baranska D., Pastorczak A., Wegner O., Kostrzewska M., Laguna P., Borowiec M., Mlynarski W. Novel severe hemophilia A and moyamoya (SHAM) syndrome caused by Xq28 deletions encompassing F8 and BRCC3 genes. Blood. 2014; 123 (25): 4002–4. https://doi.org/10.1182/blood-2014-02-553685.