Association of FMR1 repeat size with ovarian dysfunction

Sullivan, Amy K.; Marcus, Michele; Epstein, Michael P.; Allen, Emily G.; Anido, Aimee; Paquin, Jasmine; Yadav-Shah, Maneesha; Sherman, Stephanie L.

doi:10.1093/humrep/deh635

Cited by 407 publications

(408 citation statements)

References 25 publications

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“…The interesting fact about this finding is that it has also been reported for ovarian insufficiency [21][22][23][24].…”

Section: Neuropsychiatric and Muscular Involvementsupporting

confidence: 63%

“…It has been found that the risk of POI and the ovarian manifestations present on a specific patient may have a non-linear association with the number of CGG repeats, with the risk of developing ovarian insufficiency increasing with the number of repeats and then reaching a plateau or even decreasing after 80-100 CGG repeats are reached [21][22][23][24]. Allen et al (2007) [24] did a study with 948 carriers with varying repeat sizes in order to get a better view of the reproductive aging milestones among these women and its relation with the number of CGG repeats present.…”

Section: Reproductive Involvementmentioning

confidence: 99%

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Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency

Hoyos

Thakur

2016

J Assist Reprod Genet

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Fragile X premutation carriers have 55-200 CGG repeats in the 5' untranslated region of the FMR1 gene. Women with this premutation face many physical and emotional challenges in their life. Approximately 20% of these women will develop fragile X-associated primary ovarian insufficiency (FXPOI). In addition, they suffer from increased rates of menstrual dysfunction, diminished ovarian reserve, reduction in age of menopause, infertility, dizygotic twinning, and risk of having an offspring with a premutation or full mutation. Consequent chronic hypoestrogenism may result in impaired bone health and increased cardiovascular risk. Neuropsychiatric issues include risk of developing fragile X-associated tremor/ataxia syndrome, neuropathy, musculoskeletal problems, increased prevalence of anxiety, depression, and sleep disturbances independent of the stress of raising an offspring with fragile X syndrome and higher risk of postpartum depression. Some studies have reported a higher prevalence of thyroid abnormalities and hypertension in these women. Reproductive health providers play an important role in the health supervision of women with fragile X premutation. Awareness of these risks and correlation of the various manifestations could help in early diagnosis and coordination of care and services for these women and their families. This paper reviews current evidence regarding the possible conditions that may present in women with premutation-sized repeats beyond FXPOI.

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“…The interesting fact about this finding is that it has also been reported for ovarian insufficiency [21][22][23][24].…”

Section: Neuropsychiatric and Muscular Involvementsupporting

confidence: 63%

Section: Reproductive Involvementmentioning

confidence: 99%

Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency

Hoyos

Thakur

2016

J Assist Reprod Genet

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“…Roughly 20% of female Fmr1 premutation carriers develop a condition known as premature ovarian failure (POF; Sherman, 2000). The disorder is characterized by earlier menopause in premutation carriers compared to non-carriers (Murray et al, 2000;Hundscheid et al, 2001) and risk for POF significantly increases if the CGG repeat size exceeds 80 repeats (Sullivan et al, 2005). In contrast, the risk of developing POF in women without the premutation allele (non-carriers) is only 1% (Murray et al, 2000).…”

Section: The Fragile X Mental Retardation Gene and Proteinmentioning

confidence: 99%

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

et al. 2010

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The purpose of this study was to examine the expression of GABAergic proteins in Fmr1 knockout mice during brain maturation and to assess behavioural changes potentially linked to perturbations in the GABAergic system. Quantitative western blotting of the forebrain revealed that compared to wild-type mice, the GABA A receptor α1, β2, and δ subunits, and the GABA catabolic enzymes GABA transaminase and SSADH were down-regulated during postnatal development, while GAD65 was up-regulated in the adult knockout mouse forebrain. In tests of locomotor activity, the suppressive effect on motor activity of the GABA A β2/3 subunit-selective drug loreclezole was impaired in the mutant mice. In addition, sleep time induced by the GABA A β2/3-selective anaesthetic drug etomidate was decreased in the knockout mice. Our results indicate that disruptions in the GABAergic system in the developing brain may result in behavioural consequences in adults with fragile X syndrome.iii

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“…A link has been suggested between pituitary inclusions and dysregulated neuroendocrine function in patients with FXTAS. Increased Follicle Stimulating Hormone (FSH) (Hundscheid et al, 2001;Sullivan et al, 2005;Greco et al, 2007) and decreased inhibin A and B levels in female PM carriers were reported even in those who are cycling normally, suggestive of early ovarian aging and ovarian compromise (Welt et al, 2004). Elevated levels of FSH have been found to reflect decreasing ovarian reserve (MacNaughton et al, 1992), which can be correlated to the risk of developing POF seen in female PM carriers.…”

Section: Introductionmentioning

confidence: 99%

Altered hypothalamus–pituitary–adrenal gland axis regulation in the expanded CGG-repeat mouse model for fragile X-associated tremor/ataxia syndrome

Brouwer

Severijnen

Jong

et al. 2008

Psychoneuroendocrinology

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The human FMR1 gene contains an unstable CGG-repeat in its 5′ untranslated region. The repeat length in the normal population is polymorphic (5-54 CGG-repeats). Individuals carrying lengths beyond 200 CGGs (i.e. the full mutation) show hypermethylation and as a consequence gene silencing of the FMR1 gene. The absence of the gene product FMRP causes the fragile X syndrome, the most common inherited form of mental retardation. Elderly carriers of the premutation (PM), which is defined as a repeat length between 55-200 CGGs, can develop a progressive neurodegenerative syndrome: fragile X-associated tremor/ataxia syndrome (FXTAS). The high FMR1 mRNA levels observed in cells from PM carriers have led to the hypothesis that FXTAS is caused by a pathogenic RNA gain-of-function mechanism. Apart from tremor/ataxia, specific psychiatric symptoms have been described in PM carriers with or without FXTAS. Since these symptoms could arise from elevated stress hormone levels, we investigated hypothalamicpituitary-adrenal (HPA) axis regulation using a knock-in mouse model with an expanded CGGrepeat in the PM range (>98 repeats) in the Fmr1 gene, which shows repeat instability, and displays biochemical, phenotypic and neuropathological characteristics of FXTAS. We show elevated levels of corticosterone in serum and ubiquitin-positive inclusions in both the pituitary and adrenal gland of 100-week old animals. In addition, we demonstrate ubiquitin-positive © 2008 Elsevier Ltd. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Financial disclosuresWe declare no conflict of interest. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript inclusions in the amygdala from aged expanded CGG-repeat mice. We hypothesize that altered regulation of the HPA axis and the amygdala and higher stress hormone levels in the mouse model for FXTAS may explain associated psychological symptoms in humans.

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Association of FMR1 repeat size with ovarian dysfunction

Cited by 407 publications

References 25 publications

Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency

Fragile X premutation in women: recognizing the health challenges beyond primary ovarian insufficiency

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

Altered hypothalamus–pituitary–adrenal gland axis regulation in the expanded CGG-repeat mouse model for fragile X-associated tremor/ataxia syndrome

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