Review Article
Volume 11 Issue 7 - 2022
New Insights into the Mechanism of Pathogenesis of Fragile X-Associated Premature Ovarian Failure
Ranjana Rana, Mona Sharma and Ashutosh Halder*
Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India
*Corresponding Author: Ashutosh Halder, Professor and Head, Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, Delhi, India.
Received: June 09, 2022; Published: June 29, 2022




Abstract

One of the common genetic defects linked to Premature Ovarian Failure is FMR1 gene premutation (trinucleotide repeats). However, it is unclear how this trinucleotide repeats number produces ovarian failure phenotype. The aim of this review is to highlight the advances made in understanding the mechanism by which FMR1 premutation causes POF. POF due to FMR1 gene premutation may be caused by three mechanisms: RNA toxic gain-of-function, repeat-associated non-AUG translation creating cryptic protein FMRpolyG, and transcription of lncRNAs, particularly FMR4 and FMR6, which have been linked to FMR1 instability and ovarian dysfunction.

Keywords: FMR1 Premutation; Premature Ovarian Failure; RNA Toxicity; Non-AUG Translation; Long Non-Coding RNA

References

  1. Wittenberger MD., et al. “The FMR1 premutation and reproduction”. Fertility and Sterility3 (2007): 456-465.
  2. Elizur SE., et al. “Pathophysiology Mechanisms in Fragile-X Primary Ovarian Insufficiency”. Methods in Molecular Biology 1942 (2019): 165-171.
  3. Welt CK. “Primary ovarian insufficiency: a more accurate term for premature ovarian failure”. Clinical Endocrinology4 (2008): 499-509.
  4. Qin Y., et al. “Genetics of primary ovarian insufficiency: new developments and opportunities”. Human Reproduction Update 6 (2015): 787-808.
  5. Berletch JB., et al. “Escape from X Inactivation Varies in Mouse Tissues”. PLOS Genetics3 (2015): e1005079.
  6. Goswami D and Conway GS. “Premature ovarian failure”. Human Reproduction Update4 (2005): 391-410.
  7. Huang C., et al. “Meiotic Recombination Defects and Premature Ovarian Insufficiency”. Frontiers in Cell and Developmental Biology (2021): 9.
  8. Vujović S., et al. “Premature ovarian failure”. Srpski Arhiv za Celokupno Lekarstvo11-12 (2012): 806-811.
  9. Sharma M and Halder A. EC GYNAECOLOGY EC GYNAECOLOGY Review Article Understanding Basic Concepts of Premature Ovarian Failure 10.11 (2021): 25-36.
  10. Sherman SL. “Premature ovarian failure in the fragile X syndrome”. American Journal of Medical Genetics3 (2000): 189-194.
  11. Marozzi A., et al. “Association between idiopathic premature ovarian failure and fragile X premutation”. Human Reproduction1 (2000): 197-202.
  12. Gersak K., et al. “Fragile X premutation in women with sporadic premature ovarian failure in Slovenia”. Human Reproduction8 (2003): 1637-1640.
  13. Guo T., et al. “FMR1 premutation is an uncommon explanation for premature ovarian failure in Han Chinese”. PloS One7 (2014): e103316.
  14. Dean DD., et al. “Molecular Characterization of FMR1 Gene by TP-PCR in Women of Reproductive Age and Women with Premature Ovarian Insufficiency”. Molecular Diagnosis and Therapy1 (2018): 91-100.
  15. Allen EG., et al. “Examination of reproductive aging milestones among women who carry the FMR1 premutation”. Human Reproduction8 (2007): 2142-2152.
  16. Johnson K., et al. “Fragile X Premutation Associated Conditions (FXPAC)”. Frontiers in Pediatrics (2020): 8.
  17. Fu YH., et al. “Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox”. Cell6 (1991): 1047-1058.
  18. Allen EG., et al. “Refining the risk for fragile X-associated primary ovarian insufficiency (FXPOI) by FMR1 CGG repeat size”. The Journal of Genetic Medicine American College of Medical Genetics9 (2021): 1648-1655.
  19. Pastore LM and Johnson J. “The FMR1 gene, infertility, and reproductive decision-making: a review”. Frontiers in Genetics 5 (2014): 195.
  20. Spath MA., et al. “X chromosome inactivation does not define the development of premature ovarian failure in fragile X premutation carriers”. American Journal of Medical Genetics2 (2010): 387-393.
  21. Spath MA., et al. “Predictors and risk model development for menopausal age in fragile X premutation carriers”. The Journal of Genetic Medicine American College of Medical Genetics7 (2011): 643-650.
  22. Bidet M., et al. “Resumption of ovarian function and pregnancies in 358 patients with premature ovarian failure”. The Journal of Clinical Endocrinology and Metabolism12 (2011): 3864-3872.
  23. Nelson LM., et al. “An update: spontaneous premature ovarian failure is not an early menopause”. Fertility and Sterility5 (2005): 1327-1332.
  24. Kenneson A., et al. “Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers”. Human Molecular Genetics14 (2001): 1449-1454.
  25. Oostra BA and Willemsen R. “A fragile balance: FMR1 expression levels”. Human Molecular Genetics 2 (2003): R249-257.
  26. Tassone F., et al. “FMR1 RNA within the intranuclear inclusions of fragile X-associated tremor/ataxia syndrome (FXTAS)”. RNA Biology2 (2004): 103-105.
  27. Sellier C., et al. “Sam68 sequestration and partial loss of function are associated with splicing alterations in FXTAS patients”. The EMBO Journal7 (2010): 1248-1261.
  28. Pretto DI., et al. “CGG allele size somatic mosaicism and methylation in FMR1 premutation alleles”. Journal of Medical Genetics5 (2014): 309-318.
  29. Sullivan AK., et al. “Association of FMR1 repeat size with ovarian dysfunction”. Human Reproduction2 (2005): 402-412.
  30. Lekovich J., et al. “CGG repeat length and AGG interruptions as indicators of fragile X-associated diminished ovarian reserve”. Medical Genetics, Part C of the American Journal of Medical Genetics9 (2018): 957-964.
  31. Elizur SE., et al. “Elevated levels of FMR1 mRNA in granulosa cells are associated with low ovarian reserve in FMR1 premutation carriers”. PLOS One8 (2014): e105121.
  32. Friedman-Gohas M., et al. “Dysregulation of anti-Mullerian hormone expression levels in mural granulosa cells of FMR1 premutation carriers”. Scientific Reports1 (2021): 14139.
  33. Sellier C., et al. “Sam68 sequestration and partial loss of function are associated with splicing alterations in FXTAS patients”. The EMBO Journal7 (2010): 1248-1261.
  34. Bianchi E., et al. “Ablation of the Sam68 gene impairs female fertility and gonadotropin-dependent follicle development”. Human Molecular Genetics24 (2010): 4886-4894.
  35. Friedman-Gohas M., et al. “Dysregulation of anti-Mullerian hormone expression levels in mural granulosa cells of FMR1 premutation carriers”. Scientific Reports1 (2021): 14139.
  36. Kearse MG and Wilusz JE. “Non-AUG translation: a new start for protein synthesis in eukaryotes”. Genes and Development17 (2017): 1717-1731.
  37. Zu T., et al. “Non-ATG-initiated translation directed by microsatellite expansions”. Proceedings of the National Academy of Sciences of the United States of America1 (2011): 260-265.
  38. Friedman-Gohas M., et al. “FMRpolyG accumulates in FMR1 premutation granulosa cells”. Journal of Ovarian Research1 (2020): 22.
  39. Nguyen XP., et al. “P-514 RAN-Translation in Fragile X associated Premature Ovarian Insufficiency (FXPOI): FMRpolyG as a predictive tool”. Human Reproduction1 (2021): deab130.513.
  40. Yao RW., et al. “Cellular functions of long noncoding RNAs”. Nature Cell Biology5 (2019): 542-551.
  41. Huang G., et al. “Long Noncoding RNA Can Be a Probable Mechanism and a Novel Target for Diagnosis and Therapy in Fragile X Syndrome”. Frontiers in Genetics 10 (2019): 446.
  42. Elizur SE., et al. “FMR6 may play a role in the pathogenesis of fragile X-associated premature ovarian insufficiency”. Gynecological Endocrinology of Journal International Society of Gynecological Endocrinology4 (2016): 334-337.
Citation: Ashutosh Halder., et al. “New Insights into the Mechanism of Pathogenesis of Fragile X-Associated Premature Ovarian Failure”. EC Gynaecology 11.7 (2022): 38-43.

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