A homozygous NOP14 variant is likely to cause recurrent pregnancy loss

Abstract

Recurrent pregnancy loss is newly defined as more than two consecutive miscarriages. Recurrent pregnancy loss occurs in <5% of total pregnancies. The cause in approximately 40–60% of recurrent pregnancy loss cases remains elusive and must be determined. We investigated two unrelated Iranian consanguineous families with recurrent pregnancy loss. We performed exome sequencing using DNA from a miscarriage tissue and identified a homozygous NOP14 missense variant (c.[136C>G];[136C>G]) in both families. NOP14 is an evolutionally conserved protein among eukaryotes and is required for 18S rRNA processing and 40S ribosome biogenesis. Interestingly, in zebrafish, homozygous mutation of nop14 (possibly loss of function) resulting from retrovirus-mediated insertional mutagenesis led to embryonic lethality at 5 days after fertilization, mimicking early pregnancy loss in humans. Similarly, it is known that the nop14-null yeast is inviable. These data suggest that the homozygous NOP14 mutation is likely to cause recurrent pregnancy loss. Furthermore, this study shows that exome sequencing is very useful to determine the etiology of unsolved recurrent pregnancy loss.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2

References

  1. 1.

    Practice Committee of the American Society for Reproductive M. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril. 2012;98:1103–11.

  2. 2.

    Rai R, Regan L. Recurrent miscarriage. Lancet (Lond, Engl). 2006;368:601–11.

  3. 3.

    Garrido-Gimenez C, Alijotas-Reig J. Recurrent miscarriage: causes, evaluation and management. Postgrad Med J. 2015;91:151–62.

  4. 4.

    Kato K, Aoyama N, Kawasaki N, Hayashi H, Xiaohui T, Abe T, et al. Reproductive outcomes following preimplantation genetic diagnosis using fluorescence in situ hybridization for 52 translocation carrier couples with a history of recurrent pregnancy loss. J Hum Genet. 2016;61:687–92.

  5. 5.

    Diejomaoh MF. Recurrent spontaneous miscarriage is still a challenging diagnostic and therapeutic quagmire. Med Princ Pract. 2015;24 Suppl 1:38–55.

  6. 6.

    Shamseldin HE, Swaid A, Alkuraya FS. Lifting the lid on unborn lethal Mendelian phenotypes through exome sequencing. Genet Medt. 2013;15:307–9.

  7. 7.

    Filges I, Nosova E, Bruder E, Tercanli S, Townsend K, Gibson WT, et al. Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype. Clin Genet. 2014;86:220–8.

  8. 8.

    Tsurusaki Y, Yonezawa R, Furuya M, Nishimura G, Pooh RK, Nakashima M, et al. Whole exome sequencing revealed biallelic IFT122 mutations in a family with CED1 and recurrent pregnancy loss. Clin Genet. 2014;85:592–4.

  9. 9.

    Ellard S, Kivuva E, Turnpenny P, Stals K, Johnson M, Xie W, et al. An exome sequencing strategy to diagnose lethal autosomal recessive disorders. Eur J Human Genet. 2015;23:401–4.

  10. 10.

    Tsurusaki Y, Koshimizu E, Ohashi H, Phadke S, Kou I, Shiina M, et al. De novo SOX11 mutations cause Coffin–Siris syndrome. Nat Commun. 2014;5:4011.

  11. 11.

    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.

  12. 12.

    Higasa K, Miyake N, Yoshimura J, Okamura K, Niihori T, Saitsu H, et al. Human genetic variation database, a reference database of genetic variations in the Japanese population. J Hum Genet. 2016;61:547–53.

  13. 13.

    Scott EM, Halees A, Itan Y, Spencer EG, He Y, Azab MA, et al. Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery. Nat Genet. 2016;48:1071–6.

  14. 14.

    Miyatake S, Koshimizu E, Fujita A, Fukai R, Imagawa E, Ohba C, et al. Detecting copy-number variations in whole-exome sequencing data using the eXome Hidden Markov Model: an ‘exome-first’ approach. J Hum Genet. 2015;60:175–82.

  15. 15.

    Liu PC, Thiele DJ. Novel stress-responsive genes EMG1 and NOP14 encode conserved, interacting proteins required for 40S ribosome biogenesis. Mol Biol Cell. 2001;12:3644–57.

  16. 16.

    Henras AK, Plisson-Chastang C, O’Donohue MF, Chakraborty A, Gleizes PE. An overview of pre-ribosomal RNA processing in eukaryotes. Wiley Interdiscip Rev RNA. 2015;6:225–42.

  17. 17.

    Amsterdam A, Burgess S, Golling G, Chen W, Sun Z, Townsend K, et al. A large-scale insertional mutagenesis screen in zebrafish. Genes Dev. 1999;13:2713–24.

  18. 18.

    Amsterdam A, Nissen RM, Sun Z, Swindell EC, Farrington S, Hopkins N. Identification of 315 genes essential for early zebrafish development. Proc Natl Acad Sci USA. 2004;101:12792–7.

  19. 19.

    Burns CE, Galloway JL, Smith AC, Keefe MD, Cashman TJ, Paik EJ, et al. A genetic screen in zebrafish defines a hierarchical network of pathways required for hematopoietic stem cell emergence. Blood. 2009;113:5776–82.

  20. 20.

    Tuller G, Prein B, Jandrositz A, Daum G, Kohlwein SD. Deletion of six open reading frames from the left arm of chromosome IV of Saccharomyces cerevisiae. Yeast. 1999;15:1275–85.

  21. 21.

    Warda AS, Freytag B, Haag S, Sloan KE, Gorlich D, Bohnsack MT. Effects of the Bowen–Conradi syndrome mutation in EMG1 on its nuclear import, stability and nucleolar recruitment. Hum Mol Genet. 2016;25:5353–64.

  22. 22.

    Armistead J, Khatkar S, Meyer B, Mark BL, Patel N, Coghlan G, et al. Mutation of a gene essential for ribosome biogenesis, EMG1, causes Bowen–Conradi syndrome. Am J Hum Genet. 2009;84:728–39.

  23. 23.

    Brothman AR, Schneider NR, Saikevych I, Cooley LD, Butler MG, Patil S, et al. Cytogenetic heteromorphisms: survey results and reporting practices of giemsa-band regions that we have pondered for years. Arch Pathol Lab Med. 2006;130:947–9.

  24. 24.

    Fonatsch C. New chromosome polymorphism: inv(16)(p11q12 or 13). Cytogenet Cell Genet. 1977;18:106–7.

  25. 25.

    Miller K. Pericentric inversion 16 in man—a second case. Clin Genet. 1986;29:181–2.

  26. 26.

    Verma RS, Dosik H, Lubs HA. Size and pericentric inversion heteromorphisms of secondary constriction regions (h) of chromosomes 1, 9, and 16 as detected by CBG technique in Caucasians: classification, frequencies, and incidence. Am J Med Genet. 1978;2:331–9.

  27. 27.

    Sahin FI, Yilmaz Z, Yuregir OO, Bulakbasi T, Ozer O, Zeyneloglu HB. Chromosome heteromorphisms: an impact on infertility. J Assist Reprod Genet. 2008;25:191–5.

  28. 28.

    Caglayan AO, Ozyazgan I, Demiryilmaz F, Ozgun MT. Are heterochromatin polymorphisms associated with recurrent miscarriage? J Obstet Gynaecol Res. 2010;36:774–6.

  29. 29.

    Akbas H, Isi H, Oral D, Turkyilmaz A, Kalkanli-Tas S, Simsek S, et al. Chromosome heteromorphisms are more frequent in couples with recurrent abortions. Genet Mol Res. 2012;11:3847–51.

Download references

Acknowledgements

We thank all the patients and their families for their participation in this study. We also thank Nobuko Watanabe for her technical assistance. This work was supported by grants from Research on Measures for Intractable Diseases; Comprehensive Research on Disability Health and Welfare, the Strategic Research Program for Brain Science; Initiative on Rare and Undiagnosed Diseases in Pediatrics and Initiative on Rare and Undiagnosed Diseases for Adults from the Japan Agency for Medical Research and Development; Grants-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Ministry of Education, Science, Sports and Culture of Japan; Grants-in-Aid for Scientific Research (A and B) from the Japan Society for the Promotion of Science; Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from the Japan Science and Technology Agency; grants from the Ministry of Health, Labor and Welfare; the Takeda Science Foundation; the Yokohama Foundation for Advancement of Medical Science; and the Hayashi Memorial Foundation for Female Natural Scientists.

Author information

Correspondence to Naomichi Matsumoto or Noriko Miyake.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Supporting information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading