Fragile X‐associated primary ovarian insufficiency: evidence for additional genetic contributions to severity

Hunter, Jessica Ezzell; Epstein, Michael P.; Tinker, Stuart W.; Charen, Krista; Sherman, Stephanie L.

doi:10.1002/gepi.20329

Cited by 38 publications

(34 citation statements)

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“…Clear genetic association has been identified in 11 cases, and the investigation in siblings of the remaining 30 families revealed female sex preponderance, indicating that X chromosome defect is an important cause of familial premature ovarian failure. In 2008, Hunter et al [22] compared women from 225 families with a history of fragile X syndrome with women from families in the general population, and reported significant familial aggregation of age at menopause with an estimated additive genetic variance of 0.55-0.96. Adjustment for FMR1 repeat size and confounders is performed.…”

Section: Etiologic Mechanisms Of Primary Ovarian Insufficiencymentioning

confidence: 99%

“…Mutations of FMR1 can lead to the expansion of a polymorphic CGG repeat in the 5′ untranslated region, which can become unstable and expand in length from generation to generation [22]. According to the count of repeats, alleles are classified in four types, normal range (2634 repeats), intermediate (3554 repeats), premutation (55199 repeats), and full mutation (greater than 200 repeats) [31].…”

Section: Poi Genes On X Chromosomementioning

confidence: 99%

“…When there is a full mutation, the gene is silenced by methylation, resulting in the absence of FMR protein (FMRP) expression, which causes mental retardation. Premutations of FMR1 gene, especially those with ~8099 repeats, are the most common discovered genetic cause of spontaneous 46, XX POI, and the resultant POI is named the fragile X-related primary ovarian insufficiency (FXPOI) [6,17,22,32]. Premutation alleles remain unmethylated, and lead to increased FMR1 transcription and decreased levels of FMRP [22].…”

Section: Poi Genes On X Chromosomementioning

confidence: 99%

“…Premutations of FMR1 gene, especially those with ~8099 repeats, are the most common discovered genetic cause of spontaneous 46, XX POI, and the resultant POI is named the fragile X-related primary ovarian insufficiency (FXPOI) [6,17,22,32]. Premutation alleles remain unmethylated, and lead to increased FMR1 transcription and decreased levels of FMRP [22]. Premutation alleles occur in ~7% of sporadic POI and ~21% in familial POI, significantly higher than in general population [33,34].…”

Section: Poi Genes On X Chromosomementioning

confidence: 99%

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An update on primary ovarian insufficiency

Jin

Huang

2012

Sci. China Life Sci.

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Primary ovarian insufficiency (POI) occurs in about 1% of female population under the age of 40, leading to reproductive problems, an earlier encounter with menopausal symptoms, and complicated diseases. There are three presumable mechanisms involved in the development of POI, namely apoptosis acceleration, follicular maturation blocking and premature follicle activation, through the following studied causes: (i) chromosomal abnormalities or gene mutations: mostly involve X chromosome, such as FMR1 premutation; more and more potentially causal genes have been screened recently; (ii) metabolic disorders such as classic galactosaemia and 17-OH deficiency; (iii) autoimmune mediated ovarian damage: observed alone or with some certain autoimmune disorders and syndromes; but the specificity and sensitivity of antibodies towards ovary are still questionable; (iv) iatrogenic: radiotherapy or chemotherapy used in cancer treatment, as well as pelvic surgery with potential threat to ovaries' blood supply can directly damage ovarian function; (v) virus infection such as HIV and mumps; (vi) toxins and other environmental/lifestyle factors: cigarette smoking, toxins (e.g., 4-vinylcyclohexene diepoxide), and other environmental factors are associated with the development of POI. The etiology of a majority of POI cases is not identified, and is believed to be multifactorial. Strategies to POI include hormone replacement and infertility treatment. Assisted conception with donated oocytes has been proven to achieve pregnancy in POI women. Embryo cryopreservation, ovarian tissue cryopreservation and oocyte cryopreservation have been used to preserve ovarian reserve in women undergoing cancer treatments. Primary ovarian insufficiency (POI), commonly referred to as premature ovarian failure (POF), is defined as the occurrence of amenorrhea (for 4 months or more) before the age of 40 in women, accompanied with an increase of serum FSH to menopausal level (usually over 40 IU L 1 , obtained at least 1 month apart), and estradiol levels less than 50 pg mL 1 (which indicate hypoestrogenism) [1]. Primary ovarian insufficiency is first brought to light by Fuller Albright in 1942, who emphasized that the end stage of ovarian function is the primary defect rather than abnormality in gonadotropin secretion [2], and avoided the discomforting and inaccurate stressing on "failure", like death-sentence for ovarian function and conception.Menopause is a destined phase of women, which is expected to occur at around the age of (50±4) years in US women [3]. The age of 40 is two standard deviations below this average [4]. With an incidence of 1% in women under the age of 40, and 0.1% in women under the age of 30 [5], POI renders patients estrogen deficiency and anovulation, resulting in vasomotor symptoms (hot flashes and night sweats), atrophic vaginitis, dyspareunia, primary or secondary amenorrhea, and infertility. 76% of POI cases developed after normal puberty and establishment of regular menses [6]. Some of such conditions occur after stopping...

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Section: Etiologic Mechanisms Of Primary Ovarian Insufficiencymentioning

confidence: 99%

Section: Poi Genes On X Chromosomementioning

confidence: 99%

Section: Poi Genes On X Chromosomementioning

confidence: 99%

Section: Poi Genes On X Chromosomementioning

confidence: 99%

See 2 more Smart Citations

An update on primary ovarian insufficiency

Jin

Huang

2012

Sci. China Life Sci.

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“…Untersuchungen zum Menopausenalter und anderen Symptomen einer FXPOI an FamilienmitglieZusammenfassung · Abstract dern von Prämutationsträgerinnen legen nahe, dass weitere genetische Faktoren Art und Ausmaß von FXPOI beeinflussen[14,17].Bei Verdacht auf POI müssen mögliche Ursachen abgeklärt werden, da sich diese ggf. systemisch auf andere Organe, auf die…”

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Frühzeitige Ovarialinsuffizienz und FMR1-Mutation

Schröer

2012

Gynäkologe

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Unstable Mutations in the FMR1 Gene and the Phenotypes

Loesch

Hagerman

2012

Advances in Experimental Medicine and Biology

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Fragile X syndrome (FXS), a severe neurodevelopmental anomaly, and one of the earliest disorders linked to an unstable ('dynamic') mutation, is caused by the large (>200) CGG repeat expansions in the noncoding portion of the FMR1 (Fragile X Mental Retardation-1) gene. These expansions, termed full mutations, normally silence this gene's promoter through methylation, leading to a gross deficit of the Fragile X Mental Retardation Protein (FMRP) that is essential for normal brain development. Rare individuals with the expansion but with an unmethylated promoter (and thus, FMRP production), present a much less severe form of FXS.However, a unique feature of the relationship between the different sizes of CGG expanded tract and phenotypic changes is that smaller expansions (<200) generate a series of different clinical manifestations and/or neuropsychological changes. The major part of this chapter is devoted to those FMR1 alleles with small (55-200) CGG expansions, termed 'premutations', which have the potential for generating the full mutation alleles on mother-offspring transmission, on the one hand, and are associated with some phenotypic changes, on the other. Thus, the role of several factors known to determine the rate of CGG expansion in the premutation alleles is discussed first. Then, an account of various neurodevelopmental, congnitive, behavioural and physical changes reported in carriers of these small expansions is given, and possible association of these conditions with a toxicity of the elevated FMR1 gene's transcript (mRNA) is discussed.The next two sections are devoted to major and well defined clinical conditions associated with the premutation alleles. The first one is the late onset neurodegenerative disorder termed fragile Xassociated tremor ataxia syndrome (FXTAS). The wide range of clinical and neuropsychological manifestations of this syndrome, and their relevance to elevated levels of the FMR1 mRNA, are described. Another distinct disorder linked to the CGG repeat expansions within the premutation range is fragile X-associated primary ovarian insufficiency (FXPOI) in females, and an account of the spectrum of manifestations of this disorder, together with the latest findings suggesting an early onset of the ovarian changes, is given.In the following section, the most recent findings concerning the possible contribution of FMR1 'grey zone' alleles (those with the smallest repeat expansions overlapping with the normal range

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Fragile X‐associated primary ovarian insufficiency: evidence for additional genetic contributions to severity

Cited by 38 publications

References 34 publications

An update on primary ovarian insufficiency

An update on primary ovarian insufficiency

Frühzeitige Ovarialinsuffizienz und FMR1-Mutation

Unstable Mutations in the FMR1 Gene and the Phenotypes

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