Evaluation of FMR1 gene mutations in Turkish women newly diagnosed with primary ovarian failure
DOI:
https://doi.org/10.18203/2320-1770.ijrcog20190262Keywords:
Fragile X syndrome, Premature ovarian insufficiency, Premutation, PrevalenceAbstract
Background: One of the known causes of ovarian dysfunction is fragile X mental retardation gene 1 (FMR1) premutation. The prevalence of FMR1 premutation in primary ovarian failure (POF) cases may differ between the studies due to some reasons including POF definition, definition of premutation, and determination of study population, ethnicity, genetic and environmental factors. In this study authors aimed to determine the prevalence of FMR1 mutations in patients who applied to present clinic and diagnosed as POF.
Methods: This retrospective cohort study was conducted on 200 women who had been newly diagnosed with POF in present clinic between 2013 and 2014. The presence of cytogenetic fragility was firstly investigated in all patients by using the lymphocyte culture method, and molecular analysis of the FMR1 gene was then performed. Genomic DNA’s of cases were isolated using standard protocols, followed by polymerase chain reaction amplification with an appropriate program. Fragment analysis of the amplification products were performed by agarose gel electrophoresis.
Results: Cytogenetic analysis results in 200 cases were numerically and structurally normal in all patients, and as a result of molecular genetic analysis of FMR1 gene; 1 (0.5%) patient had complete mutation and 9 (4.5%) patients had premutation carriage.
Conclusions: FMR1 gene mutations are common in women with POF. These mutations should be investigated in all patients presenting with POF, particularly in cases with early onset and family history of POF, and also genetic counseling should be given to those patients.
References
ESHRE Guideline Group on POI, Webber L, Davies M, Anderson R, Bartlett J, Braat D, Cartwright B, et al. ESHRE Guideline: management of women with premature ovarian insufficiency. Human Reprod. 2016;31(5):926-37.
Tokmak A, Yıldırım G, Sarıkaya E, Çınar M, Boğdaycıoğlu N, Yılmaz FM, et al. Increased oxidative stress markers may be a promising indicator of risk for primary ovarian insufficiency: a cross-sectional case control study. Brazil J Gynecol Obstet. 2015;37(9):411-6.
Ceylaner G, Altinkaya SO, Mollamahmutoglu L, Ceylaner S. Genetic abnormalities in Turkish women with premature ovarian failure. Int J Gynaecol Obstet. 2010;110:122-4.
Bussani C, Papi L, Sestini R, Baldinotti F, Bucciantini S, Bruni V, et al. Premature ovarian failure and fragile X premutation: a study on 45 women. Eur J Obstet Gynecol Reprod Biol. 2004;112(2):189-91.
Wittenberger MD, Hagerman RJ, Sherman SL, McConkie-Rosell A, Welt CK, Rebar RW, et al. The FMR1 premutation and reproduction. Fertil Steril. 2007;87(3):456-65.
Saldarriaga W, Lein P, González Teshima LY, Isaza C, Rosa L, Polyak A, et al. Phenobarbital use and neurological problems in FMR1 premutation carriers. Neurotoxicol. 2016;53:141-7.
Lu CL, Li R, Chen XN, Xu YY, Yan LY, Yan J, et al. The 'normal' range of FMR1 triple CGG repeats may be associated with primary ovarian insufficiency in China. Reprod Biomed Online. 2017;34:175-80.
Sherman SL. Premature ovarian failure in the fragile X syndrome. Am J Med Genet. 2000;97(3):189-94.
Murray A, Webb J, Grimley S, Conway G, Jacobs P. Studies of FRAXA and FRAXE in women with premature ovarian failure. J Med Genet. 1998;35(8):637-40.
Mallolas J, Duran M, Sanchez A, Jimenez D, Castellvi- Bel S, Rife M et al. Implication of the FMR1 gene in menopause: study of 147 Spanish women. Menopause. 2001;8:1006-110.
Kenneson A, Cramer DW, Warren ST. Fragile X premutations are not a major cause of early menopause. Am J Hum Genet. 1997;61(6):1362-9.
Conway GS, Payne NN, Webb J, Murray A, Jacobs PA. Fragile X premutation screening in women with premature ovarian failure. Hum Reprod. 1998;13:1184-7.
Uzielli ML, Guarducci S, Lapi E, Cecconi A, Ricci U, Ricotti G, et al. Premature ovarian failure (POF) and fragile X premutation females: from POF to to fragile X carrier identification, from fragile X carrier diagnosis to POF association data. Am J Med Genet. 1999;84:300-3.
Marozzi A, Vegetti W, Manfredini E, Tibiletti MG, Testa G, Crosignani PG, et al. Association between idiopathic premature ovarian failure and fragile X premutation. Hum Reprod. 2000;15(1):197-202.
Gersak K, Meden-Vrtovec H, Peterlin B. Fragile X premutation in women with sporadic premature ovarian failure in Slovenia. Hum Reprod. 2003;18:1637-40.
Hur CY, Choi YM, Park SH, Yoon BK, Lee KS, Na YJ, et al. Fragile X Premutation in Patients with Idiopathic Premature Ovarian Failure. Korean J Obstet Gynecol. 2003;46:978-83.
Lo TK, Lo IF, Chan WK, Tong TM, Lam ST. Chromosomal abnormalities and FMR1 gene premutation in Chinese women with premature menopause Hong Kong Med J. 2005;11:243-50.
Bodega B, Bione S, Dalprà L, Toniolo D, Ornaghi F, Vegetti W, et al. Influence of intermediate and uninterrupted FMR1 CGG expansions in premature ovarian failure manifestation. Hum Reprod. 2006;21:952-7.
Cronister A, Teicher J, Rohlfs EM, Donnenfeld A, Hallam S. Prevalence and instability of fragile X alleles: implications for offering fragile X prenatal diagnosis. Obstet Gynecol. 2008;111:596-601.
Bachelot A, Rouxel A, Massin N, Dulon J, Courtillot C, Matuchansky C, et al. POF-GIS Study Group. Phenotyping and genetic studies of 357 consecutive patients presenting with premature ovarian failure. Eur J Endocrinol. 2009;161:179-87.
Rajkiewicz M, Szlendak-Sauer K, Sulek A, Gawlik-Zawislak S, Krysa W, Radowicki S, et al. A molecular and cytogenetic investigation of FMR1 gene premutations in Polish patients with primary ovarian insufficiency. Eur J Obstet Gynecol Reprod Biol. 2011;155:176-9.
Ishizuka B, Okamoto N, Hamada N, Sugishita Y, Saito J, Takahashi N, et al. Number of CGG repeats in the FMR1 gene of Japanese patients with primary ovarian insufficiency. Fertil Steril. 2011;96:1170-4.
Ferrarini E, Russo L, Fruzzetti F, Agretti P, De Marco G, Dimida A, et al. Clinical characteristics and genetic analysis in women with premature ovarian insufficiency. Maturitas. 2013;74:61-7.
Murray A, Schoemaker MJ, Bennett CE, Ennis S, Macpherson JN, Jones M, et al. Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency. Genet Med. 2014;16:19-24.
Guo T, Qin Y, Jiao X, Li G, Simpson JL, Chen ZJ. FMR1 premutation is an uncommon explanation for premature ovarian failure in Han Chinese. PloS One. 2014;9(7):e103316.
Bouali N, Hmida D, Mougou S, Bouligand J, Lakhal B, Dimessi S, et al. Analysis of FMR1 gene premutation and X chromosome cytogenetic abnormalities in 100 Tunisian patients presenting premature ovarian failure. Ann Endocrinol (Paris). 2015;76:671-8.
Hundscheid RD, Sistermans EA, Thomas CM, Braat DD, Straatman H, Kiemeney LA, et al. Imprinting effect in premature ovarian failure confined to paternally inherited fragile X premutations. Am J Hum Genet. 2000;66(2):413-8.
Corrigan EC, Raygada MJ, Vanderhoof VH, Nelson LM. A woman with spontaneous premature ovarian failure gives birth to a child with fragile X syndrome. Fertil Steril. 2005;84(5):1508-e5.
Murray A, Webb J, Grimley S, Conway G, Jacobs P. Studies of FRAXA and FRAXE in women with premature ovarian failure. J Med Genet. 1998;35:637-40.
Machado‐Ferreira MD, Costa‐Lima MA, Boy RT, Esteves GS, Pimentel MM. Premature ovarian failure and FRAXA premutation: Positive correlation in a Brazilian survey. Am J Med Genet Part A. 2004;126(3):237-40.
