Endocrine Abstracts (2010) 22 S11.4

Genetic defects in ovarian growth/differentiation factors

Luca Persani1,2, Raffaella Rossetti1,2 & Chiara Cacciatore1,2

1Dipartimento di Scienze Mediche, Università di Milano, Milan, Italy; 2Laboratory of Experimental Endocrinology, Ist Auxologico Italiano, Milan, Italy.

The pathogenesis of premature ovarian failure (POF) is largely unknown. However, the evidence of a frequent familiarity for the anticipation of menopause among POF women supports the concept of a strong genetic component at the origin of POF. This is further supported by the findings of several candidate genes and by data coming from natural and experimental animal models. On these bases, several groups are involved in the search for markers able to predict the risk of POF. The identification of natural models, such as the sheep strains affected with female fertility disorders caused by inherited mutations of ovarian growth/differentiation factors (GDFs) and related receptors, opened novel perspectives on the mechanisms involved in ovarian folliculogenesis and on human ovarian disorders. Several studies in the last 10 years have contributed to understand the relevant role played by GDF9 and its analog BMP15 in ovarian folliculogenesis. In our lab, we have described several missense variations in the BMP15 gene of women affected with primary or secondary amenorrhea due to hypergonadotropic ovarian failure. To understand the functional impact of these variants, we have produced wild-type and variant protein in vitro and designed specific bioassays based on human granulosa cells. All variations found in the Italian and North-American POF populations were located in the part of the gene encoding the proregion or the signal peptide and several of them cause a defective production of bioactive BMP15 protein. The percentage of POF women carrying these defective BMP15 variants reaches 4–5% among more than 300 Italian POF women. The percentage of POF women carrying GDF9 variants is instead quite poor (<1%). Therefore, ovarian GDFs defects score second after FMR1 premutations among the genetic factors known to be associated with POF pathogenesis. We therefore propose to include the screening of BMP15 gene among the analyses for the prediction of POF risk.

The financial support of Telethon – Italy (Grant no. GGP09126) is gratefully acknowledged.

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