Premature ovarian failure (POF) is an heterogeneous disorder which affect 1% of women before 40 years and represents an important cause of infertility. POF is characterized by primary or secondary amenorrhea, elevated serum gonadotropin levels and hypoestrogenism. A wide spectrum of pathogenic mechanisms may lead to POF however most cases are classified as idiopathic. Recently the attention has been focused on new candidate genes encoding oocyte specific factors, such as Growth Differentiation Factor-9 (GDF9) and its homolougous BMP15. We recently reported the involvement of BMP15 mutations in a large POF series. In this study, we report results of the analysis of GDF9 gene in 180 unrelated women with idiopathic POF (age: 12-40 years, 12 primary and 168 secondary amenorrhea). Genetic analysis was performed by direct automatic sequencing of genomic DNA and led to the identification of 2 novel missense variations (c.117G>T ® p.E39D; c.362C>T ® p.T121I) in 3 heterozygous patients, both presenting with secondary amenorrhea. None of these missense substitutions were found among 100 control women with physiological menopause beyond 50 years of age. Both variations affect exon 1 of the gene and pro-region of the protein, as the previously reported BMP15 mutations. The change p.E39D was found in one sporadic case with POF at 40 years of age, suggesting a mild disruption of folliculogenesis. This mutation was predicted to alter protein folding by means of an online algorithm (NNpredict). Differently, the p.T121I was found in a sporadic (POF onset at 37 years of age) and in a familial (POF onset at 23) case. In this family, the mutation co-segregated with POF: the mother and 1 of the 2 sisters harboured the p.T121I mutation and experienced POF at 38 and 22 years, respectively. This substitution at position 121 is predicted to affect protein function by the SIFT algorithm. In conclusion, we report two novel missense variants of GDF9 gene associated with secondary amenorrhea confirming that alterations in oocyte growth/differentiation factors may cause POF and supporting the key role of paracrine action of oocyte factors in human folliculogenesis.

Identification of new variants of GDF9 gene in large cohort of women with Premature Ovarian Failure / R. Rossetti, E. Di Pasquale, B. Bodega­, S. Borgato, P. Beck-Peccoz, A. Marozzi, L. Persani. ((Intervento presentato al 26. convegno Giornate Endocrinologiche Pisane tenutosi a Pisa nel 2006.

Identification of new variants of GDF9 gene in large cohort of women with Premature Ovarian Failure

R. Rossetti;E. Di Pasquale;B. Bodega­;P. Beck-Peccoz;A. Marozzi;L. Persani
2006

Abstract

Premature ovarian failure (POF) is an heterogeneous disorder which affect 1% of women before 40 years and represents an important cause of infertility. POF is characterized by primary or secondary amenorrhea, elevated serum gonadotropin levels and hypoestrogenism. A wide spectrum of pathogenic mechanisms may lead to POF however most cases are classified as idiopathic. Recently the attention has been focused on new candidate genes encoding oocyte specific factors, such as Growth Differentiation Factor-9 (GDF9) and its homolougous BMP15. We recently reported the involvement of BMP15 mutations in a large POF series. In this study, we report results of the analysis of GDF9 gene in 180 unrelated women with idiopathic POF (age: 12-40 years, 12 primary and 168 secondary amenorrhea). Genetic analysis was performed by direct automatic sequencing of genomic DNA and led to the identification of 2 novel missense variations (c.117G>T ® p.E39D; c.362C>T ® p.T121I) in 3 heterozygous patients, both presenting with secondary amenorrhea. None of these missense substitutions were found among 100 control women with physiological menopause beyond 50 years of age. Both variations affect exon 1 of the gene and pro-region of the protein, as the previously reported BMP15 mutations. The change p.E39D was found in one sporadic case with POF at 40 years of age, suggesting a mild disruption of folliculogenesis. This mutation was predicted to alter protein folding by means of an online algorithm (NNpredict). Differently, the p.T121I was found in a sporadic (POF onset at 37 years of age) and in a familial (POF onset at 23) case. In this family, the mutation co-segregated with POF: the mother and 1 of the 2 sisters harboured the p.T121I mutation and experienced POF at 38 and 22 years, respectively. This substitution at position 121 is predicted to affect protein function by the SIFT algorithm. In conclusion, we report two novel missense variants of GDF9 gene associated with secondary amenorrhea confirming that alterations in oocyte growth/differentiation factors may cause POF and supporting the key role of paracrine action of oocyte factors in human folliculogenesis.
Settore MED/13 - Endocrinologia
Settore BIO/13 - Biologia Applicata
Identification of new variants of GDF9 gene in large cohort of women with Premature Ovarian Failure / R. Rossetti, E. Di Pasquale, B. Bodega­, S. Borgato, P. Beck-Peccoz, A. Marozzi, L. Persani. ((Intervento presentato al 26. convegno Giornate Endocrinologiche Pisane tenutosi a Pisa nel 2006.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/63866
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