Number of CGG repeats in the FMR1 gene of Japanese patients with primary ovarian insufficiency

Ishizuka, Bunpei; Okamoto, Naoki; Hamada, Naomi; Sugishita, Yodo; Saito, Juichiro; Takahashi, Noriyuki; Ogata, Tsutomu; Itoh, Masanori

doi:10.1016/j.fertnstert.2011.08.028

Cited by 26 publications

(18 citation statements)

References 35 publications

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“…Furthermore, there was no significant difference with respect to intermediate FMR1 between POF cases and controls (2.9% vs. 1.7%, P = 0.343). Similar prevalence has been drawn from Japanese POI cohorts (3.9%) [4], indicating that intermediate FMR1 does not contribute to POF in Chinese either [8], [21]. However, in some Caucasian studies the effect of intermediate FMR1 on ovarian function was controversial.…”

Section: Discussionsupporting

confidence: 65%

“…The premutation frequency was 1.6% in the only reported Japanese study [4], and 0.9% in the smaller Chinese study [12]. Therefore, FMR1 premutation seems to be an uncommon explanation for POF in Han Chinese.…”

Section: Discussionmentioning

confidence: 95%

“…Between the normal (29–31) and full mutation (>200) range, there are intermediate and premutation range, both unstable and capable of expanding to full mutation over several generations [2]. The premutation range starts with 55 repeats and ends at 199 repeats; the intermediate range remains controversial, but generally is considered 41 or 45 to 54 repeats [2], [4].…”

Section: Introductionmentioning

confidence: 99%

“…FMR1 premutation occurs more frequently in POF patients having a positive family history compared to sporadic ones (13%–16% vs. 1.6%–3.0% in British; 12.1% vs.10% in Italian) [7]–[11]. However, in POF patients from Hong Kong (China) and Japan, the frequency of FMR1 premutation was only 0.9% (1/116) and 1.6% (2/128), respectively [4], [12]. Another two studies in Indian, including 80 and 289 POF patients respectively, revealed none of them carrying FMR1 premutation [13], [14].…”

Section: Introductionmentioning

confidence: 99%

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FMR1 Premutation Is an Uncommon Explanation for Premature Ovarian Failure in Han Chinese

Guo

Qin

et al. 2014

PLoS ONE

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BackgroundIn premature ovarian failure (POF), cessation of menstruation occurs before the expected age of menopause. Approximately 1% of women are affected. FMR1 premutation was reported to be responsible for up to 3.3%–6.7% of sporadic POF and 13% of familial cases in Caucasians, while the data was absent in Chinese population. Therefore, the impact of FMR1 CGG repeat on ovarian reserve is needed to be investigated in large Chinese cohort.MethodsThe number of FMR1 CGG repeat was determined in 379 Han Chinese women with well-defined 46, XX non-syndromic sporadic POF and 402 controls. The age of menopause onset in respect to CGG repeats was further analyzed.ResultsThe frequency of FMR1 premutation in Han Chinese POF was only 0.5% (2/379), although it was higher than that in matched controls (0%, 0/402), it was much lower than that reported in Caucasian with POF (3.3%–6.7%). The prevalence of intermediate FMR1 (41–54) was not increased significantly in sporadic POF than that in controls (2.9% vs. 1.7%, P = 0.343). However, POF patients more often carried a single additional CGG repeat in a single allele than did fertile women (allele-1: 29.7 vs. 28.8, P<0.001; allele-2: 32.6 vs. 31.5, P<0.001). POF patients with both alleles of CGG repeats outside (below or above) the normal range (26–34) showed an earlier age of cessation of menses than those with two alleles within normal range (hom-high/high vs. norm: 20.4±4.8 vs. 24.7±6.4, p<0.01; hom-low/high vs. norm: 18.7±1.7 vs. 24.7±6.4, p<0.01).ConclusionsFMR1 premutation seems to be an uncommon explanation for POF in Han Chinese. However, having both alleles with CGG repeats outside the normal range might still adversely affect ovarian aging.

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

FMR1 Premutation Is an Uncommon Explanation for Premature Ovarian Failure in Han Chinese

Guo

Qin

et al. 2014

PLoS ONE

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“…These alleles have also been suggested to contribute to the etiology of disorders associated with parkinsonism (Loesch et al, 2007, 2009; Hall et al, 2011; Trost et al, 2013). Some reports have also linked these alleles to ovarian dysfunction (Bretherick et al, 2005; Bodega et al, 2006; Streuli et al, 2009; Ishizuka et al, 2011; Karimov et al, 2011; Pastore et al, 2012; Barasoain et al, 2013) although others have found no such association (Bennett et al, 2010; Voorhuis et al, 2013; Murray et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Repeat-mediated genetic and epigenetic changes at the FMR1 locus in the Fragile X-related disorders

et al. 2014

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The Fragile X-related disorders are a group of genetic conditions that include the neurodegenerative disorder, Fragile X-associated tremor/ataxia syndrome (FXTAS), the fertility disorder, Fragile X-associated primary ovarian insufficiency (FXPOI) and the intellectual disability, Fragile X syndrome (FXS). The pathology in all these diseases is related to the number of CGG/CCG-repeats in the 5′ UTR of the Fragile X mental retardation 1 (FMR1) gene. The repeats are prone to continuous expansion and the increase in repeat number has paradoxical effects on gene expression increasing transcription on mid-sized alleles and decreasing it on longer ones. In some cases the repeats can simultaneously both increase FMR1 mRNA production and decrease the levels of the FMR1 gene product, Fragile X mental retardation 1 protein (FMRP). Since FXTAS and FXPOI result from the deleterious consequences of the expression of elevated levels of FMR1 mRNA and FXS is caused by an FMRP deficiency, the clinical picture is turning out to be more complex than once appreciated. Added complications result from the fact that increasing repeat numbers make the alleles somatically unstable. Thus many individuals have a complex mixture of different sized alleles in different cells. Furthermore, it has become apparent that the eponymous fragile site, once thought to be no more than a useful diagnostic criterion, may have clinical consequences for females who inherit chromosomes that express this site. This review will cover what is currently known about the mechanisms responsible for repeat instability, for the repeat-mediated epigenetic changes that affect expression of the FMR1 gene, and for chromosome fragility. It will also touch on what current and future options are for ameliorating some of these effects.

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Stratification of the risk of ovarian dysfunction by studying the complexity of intermediate and premutation alleles of the FMR1 gene

Quilichini,

Perol,

Cuisset

et al. 2023

American J of Med Genetics Pt A

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FMR1 premutation female carriers are at risk of developing premature/primary ovarian insufficiency (POI) with an incomplete penetrance. In this study, we determined the CGG repeat size among 1095 women with diminished ovarian reserve (DOR) / POI and characterized the CGG/AGG substructure in 44 women carrying an abnormal FMR1 repeat expansion number, compared to a group of 25 pregnant women carrying an abnormal FMR1 CGG repeat size. Allelic complexity scores of the FMR1 gene were calculated and compared between the two groups. In the DOR/POI cohort, 2.1% of women presented with an intermediate repeat size and 1.9% with a premutation. Our results suggest that the risk of POI is highest in the mid‐range of CGG repeats. We observed that the allelic score is significantly higher in POI women compared to the pregnant women group (p‐value = 0.02). We suggest that a high allelic score due to more than 2 AGG interspersions in the context of an intermediate number of repetitions could favor POI. Larger studies are still needed to evaluate the relevance of this new tool for the determination of the individual risk of developing POI in women with abnormal number of CGG repeats.

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Number of CGG repeats in the FMR1 gene of Japanese patients with primary ovarian insufficiency

Cited by 26 publications

References 35 publications

FMR1 Premutation Is an Uncommon Explanation for Premature Ovarian Failure in Han Chinese

FMR1 Premutation Is an Uncommon Explanation for Premature Ovarian Failure in Han Chinese

Repeat-mediated genetic and epigenetic changes at the FMR1 locus in the Fragile X-related disorders

Stratification of the risk of ovarian dysfunction by studying the complexity of intermediate and premutation alleles of the FMR1 gene

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