Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2010) 21 S9.1

SFEBES2009 Symposia Mechanisms and management of ovarian failure (4 abstracts)

Genetic mechanisms underlying ovarian insufficiency

Ken McElreavey


Institut Pasteur, Paris, France.


Primary ovarian insufficiency (POI) describes a continuum of impaired ovarian function that includes both primary amenorrhea and premature menopause. A significant minority of the cases are familial suggesting a genetic basis for POI. Several genetic causes of syndromic and non-syndromic forms of POI have been identified. Syndromic forms are associated with monosomy X, rearrangements of Xq and mutations in the APECED, FOXL2, EIF2B, ATM and GALT genes. In non-syndromic forms, rare mutations of the FSH and LH receptor genes as well as mutations involving BMP15, FIGLA and NOBOX have been described. These account for a small minority of POI cases and the clinical relevance of some of the mutations remains unclear. NR5A1, which encodes the steroidogenic factor-1 protein, is a key transcriptional regulator of genes involved in many reproductive processes. Mutations in NR5A1 were initially described in individuals with adrenal insufficiency and subsequently in cases of 46,XY disorders of sex development (DSD) with no evidence of adrenal failure. We initially identified a variety of NR5A1 mutations in families with cases of 46,XY DSD and 46,XX POI. The mutant proteins show altered transactivation properties on target gonadal promoters. We have also identified mutations in apparently sporadic cases of POI. Several of these mutations appear to be inherited and may be present at low frequencies in specific populations indicating possible founder origins. Some sporadic cases also have somatic anomalies. Therefore, in the case of NR5A1 mutations, the distinction between syndromic and non-syndromic forms of POI may be blurred. Our understanding of the role of NR5A1 in gonad development and function is further compounded by the spectrum of gonadal phenotypes that can be associated with the same mutation. Several new phenotypes linked to NR5A1 mutations, which were originally identified in individuals with POI, will be presented.

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