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


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


  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.

PubMed Indexed Article

EC Pharmacology and Toxicology
LC-UV-MS and MS/MS Characterize Glutathione Reactivity with Different Isomers (2,2' and 2,4' vs. 4,4') of Methylene Diphenyl-Diisocyanate.

PMID: 31143884 [PubMed]

PMCID: PMC6536005

EC Pharmacology and Toxicology
Alzheimer's Pathogenesis, Metal-Mediated Redox Stress, and Potential Nanotheranostics.

PMID: 31565701 [PubMed]

PMCID: PMC6764777

EC Neurology
Differences in Rate of Cognitive Decline and Caregiver Burden between Alzheimer's Disease and Vascular Dementia: a Retrospective Study.

PMID: 27747317 [PubMed]

PMCID: PMC5065347

EC Pharmacology and Toxicology
Will Blockchain Technology Transform Healthcare and Biomedical Sciences?

PMID: 31460519 [PubMed]

PMCID: PMC6711478

EC Pharmacology and Toxicology
Is it a Prime Time for AI-powered Virtual Drug Screening?

PMID: 30215059 [PubMed]

PMCID: PMC6133253

EC Psychology and Psychiatry
Analysis of Evidence for the Combination of Pro-dopamine Regulator (KB220PAM) and Naltrexone to Prevent Opioid Use Disorder Relapse.

PMID: 30417173 [PubMed]

PMCID: PMC6226033

EC Anaesthesia
Arrest Under Anesthesia - What was the Culprit? A Case Report.

PMID: 30264037 [PubMed]

PMCID: PMC6155992

EC Orthopaedics
Distraction Implantation. A New Technique in Total Joint Arthroplasty and Direct Skeletal Attachment.

PMID: 30198026 [PubMed]

PMCID: PMC6124505

EC Pulmonology and Respiratory Medicine
Prevalence and factors associated with self-reported chronic obstructive pulmonary disease among adults aged 40-79: the National Health and Nutrition Examination Survey (NHANES) 2007-2012.

PMID: 30294723 [PubMed]

PMCID: PMC6169793

EC Dental Science
Important Dental Fiber-Reinforced Composite Molding Compound Breakthroughs

PMID: 29285526 [PubMed]

PMCID: PMC5743211

EC Microbiology
Prevalence of Intestinal Parasites Among HIV Infected and HIV Uninfected Patients Treated at the 1o De Maio Health Centre in Maputo, Mozambique

PMID: 29911204 [PubMed]

PMCID: PMC5999047

EC Microbiology
Macrophages and the Viral Dissemination Super Highway

PMID: 26949751 [PubMed]

PMCID: PMC4774560

EC Microbiology
The Microbiome, Antibiotics, and Health of the Pediatric Population.

PMID: 27390782 [PubMed]

PMCID: PMC4933318

EC Microbiology
Reactive Oxygen Species in HIV Infection

PMID: 28580453 [PubMed]

PMCID: PMC5450819

EC Microbiology
A Review of the CD4 T Cell Contribution to Lung Infection, Inflammation and Repair with a Focus on Wheeze and Asthma in the Pediatric Population

PMID: 26280024 [PubMed]

PMCID: PMC4533840

EC Neurology
Identifying Key Symptoms Differentiating Myalgic Encephalomyelitis and Chronic Fatigue Syndrome from Multiple Sclerosis

PMID: 28066845 [PubMed]

PMCID: PMC5214344

EC Pharmacology and Toxicology
Paradigm Shift is the Normal State of Pharmacology

PMID: 28936490 [PubMed]

PMCID: PMC5604476

EC Neurology
Examining those Meeting IOM Criteria Versus IOM Plus Fibromyalgia

PMID: 28713879 [PubMed]

PMCID: PMC5510658

EC Neurology
Unilateral Frontosphenoid Craniosynostosis: Case Report and a Review of the Literature

PMID: 28133641 [PubMed]

PMCID: PMC5267489

EC Ophthalmology
OCT-Angiography for Non-Invasive Monitoring of Neuronal and Vascular Structure in Mouse Retina: Implication for Characterization of Retinal Neurovascular Coupling

PMID: 29333536 [PubMed]

PMCID: PMC5766278

EC Neurology
Longer Duration of Downslope Treadmill Walking Induces Depression of H-Reflexes Measured during Standing and Walking.

PMID: 31032493 [PubMed]

PMCID: PMC6483108

EC Microbiology
Onchocerciasis in Mozambique: An Unknown Condition for Health Professionals.

PMID: 30957099 [PubMed]

PMCID: PMC6448571

EC Nutrition
Food Insecurity among Households with and without Podoconiosis in East and West Gojjam, Ethiopia.

PMID: 30101228 [PubMed]

PMCID: PMC6086333

EC Ophthalmology
REVIEW. +2 to +3 D. Reading Glasses to Prevent Myopia.

PMID: 31080964 [PubMed]

PMCID: PMC6508883

EC Gynaecology
Biomechanical Mapping of the Female Pelvic Floor: Uterine Prolapse Versus Normal Conditions.

PMID: 31093608 [PubMed]

PMCID: PMC6513001

EC Dental Science
Fiber-Reinforced Composites: A Breakthrough in Practical Clinical Applications with Advanced Wear Resistance for Dental Materials.

PMID: 31552397 [PubMed]

PMCID: PMC6758937

EC Microbiology
Neurocysticercosis in Child Bearing Women: An Overlooked Condition in Mozambique and a Potentially Missed Diagnosis in Women Presenting with Eclampsia.

PMID: 31681909 [PubMed]

PMCID: PMC6824723

EC Microbiology
Molecular Detection of Leptospira spp. in Rodents Trapped in the Mozambique Island City, Nampula Province, Mozambique.

PMID: 31681910 [PubMed]

PMCID: PMC6824726

EC Neurology
Endoplasmic Reticulum-Mitochondrial Cross-Talk in Neurodegenerative and Eye Diseases.

PMID: 31528859 [PubMed]

PMCID: PMC6746603

EC Psychology and Psychiatry
Can Chronic Consumption of Caffeine by Increasing D2/D3 Receptors Offer Benefit to Carriers of the DRD2 A1 Allele in Cocaine Abuse?

PMID: 31276119 [PubMed]

PMCID: PMC6604646

EC Anaesthesia
Real Time Locating Systems and sustainability of Perioperative Efficiency of Anesthesiologists.

PMID: 31406965 [PubMed]

PMCID: PMC6690616

EC Pharmacology and Toxicology
A Pilot STEM Curriculum Designed to Teach High School Students Concepts in Biochemical Engineering and Pharmacology.

PMID: 31517314 [PubMed]

PMCID: PMC6741290

EC Pharmacology and Toxicology
Toxic Mechanisms Underlying Motor Activity Changes Induced by a Mixture of Lead, Arsenic and Manganese.

PMID: 31633124 [PubMed]

PMCID: PMC6800226

EC Neurology
Research Volunteers' Attitudes Toward Chronic Fatigue Syndrome and Myalgic Encephalomyelitis.

PMID: 29662969 [PubMed]

PMCID: PMC5898812

EC Pharmacology and Toxicology
Hyperbaric Oxygen Therapy for Alzheimer's Disease.

PMID: 30215058 [PubMed]

PMCID: PMC6133268

News and Events

September Issue Release

We always feel pleasure to share our updates with you all. Here, notifying you that we have successfully released the September issue of respective journals and the latest articles can be viewed on the current issue pages.

Submission Deadline for Upcoming Issue

ECronicon delightfully welcomes all the authors around the globe for effective collaboration with an article submission for the upcoming issue of respective journals. Submissions are accepted on/before October 06, 2022.

Certificate of Publication

ECronicon honors with a "Publication Certificate" to the corresponding author by including the names of co-authors as a token of appreciation for publishing the work with our respective journals.

Best Article of the Issue

Editors of respective journals will always be very much interested in electing one Best Article after each issue release. The authors of the selected article will be honored with a "Best Article of the Issue" certificate.

Certifying for Review

ECronicon certifies the Editors for their first review done towards the assigned article of the respective journals.

Latest Articles

The latest articles will be updated immediately on the articles in press page of the respective journals.