Genes involved in human premature ovarian failure

Abstract

Premature ovarian failure (POF) is an ovarian defect characterized by the premature depletion of ovarian follicles before the age of 40 years, representing one major cause of female infertility. POF relevance is continuously growing because women tend to conceive ever more frequently in their thirties and forties. POF can present very early with a pubertal defect. More frequently, it is the end stage of an occult process (primary ovarian insufficiency, POI) affecting w1-2% of under-40 women. POI is a heterogeneous disease caused by a variety of mechanisms. Though the underlying cause remains unexplained in the majority of cases, various data indicate that POI has a strong genetic component. These data include the existence of several causal genetic defects in humans, experimental and natural models, as well as the frequent familiarity. The variable expressivity of POI defect in women of the same family may indicate that, in addition to some monogenic forms, POI may frequently be considered as a multifactorial defect resulting from the contribution of several predisposing alleles. The X chromosome-linked defects play a major role among the presently known causal defects. Here, we review the principal X-linked and autosomal genes involved in syndromic and nonsyndromic forms of POI with the wish that this list will soon become upgraded because of the discovery of novel contributing mechanisms. A better understanding of POI pathogenesis will indeed allow the construction of tests able to predict the age of menopause in women at higher risk of POI.

Genetic associations with diminished ovarian reserve: a systematic review of the literature

“…One of the known genetic causes of POI, a mutation in the FMR1 gene, has been implicated as a potential cause of DOR. Additionally, many known genetic causes of POI [10] have been implicated as being associated with DOR in mice, including autoimmune regulator gene (Aire) [23], forkhead transcription factor forkhead protein (Foxl2) [24], growth differentiation factor 9 (Gdf9) [25], and bone morphogenetic protein 15 (Bmp15) [26,27]. Here, we focused on DOR to examine the strength of evidence for the association.…”

“…The FMR1 gene is responsible for Fragile X Syndrome, a form of X-linked mental retardation, which occurs when >200 trinucleotide CGG (Cytosine Guanine Guanine) repeats are located at the 5′ untranslated region of the gene. This mutation causes hypermethylation of the promoter, resulting in complete absence of the FMR protein [10,28,29]. Although women with Fragile X Syndrome with over 200 CGG repeats do not have any form of ovarian dysfunction, those with polymorphic triplet repeats above normal (35-54 repeats) have been associated with POI [2].…”

“…Inconsistency within the literature also exists regarding the definition of many terms associated with DOR. For the purpose of this review, primary ovarian insufficiency (POI) is equivalent to premature ovarian failure (POF) [9][10][11]. POI is defined as women under age 40 with amenorrhea for at least 6 months and a day 3 FSH level in the menopausal range (>40 IU/L).…”

“…Despite an earlier age of menopause, most affected patients will not meet the definition for POI, yet some may become menopausal before the age of 45 years old. POI affects 1 % of women, whereas DOR affects a much larger portion of the infertile population [9][10][11][15][16][17][18].…”

“…It is possible that an undetermined percentage of pathologic DOR has an underlying genetic etiology, as in those women with a family history of premature and early menopause who are at increased risk for early menopause, DOR, and/or POI [2,10,21]. For example, a study examining 71 chromosomally normal patients characterized as idiopathic POI found 31 % of cases to be familial, exemplifying the large genetic basis of POI [22].…”