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Identification of New Variants of Human BMP15 Gene in a Large Cohort of Women with Premature Ovarian Failure

Departments of Medical Sciences (E.D.P., P.B.-P., L.P.) and Biology and Genetics (A.M., B.B.), University of Milan, 20100 Milan, Italy; Laboratory of Endocrinological Research (E.D.P., R.R., S.B., L.P.), Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Auxologico Italiano, 20145 Milan, Italy; Department of Biomedicine of Developing Age (L.C.), University of Bari, 70126 Bari, Italy; Department of Pediatric Endocrinology (S.E.), Regina Margherita Hospital, 10126 Turin, Italy; Pediatric Clinic (G.Ra.), Bolzano Hospital, 39100 Bolzano, Italy; Department of Pediatrics (G.Ru.), University Vita-Salute, San Raffaele, 20132 Milan, Italy; Pediatric Clinic (M.S.), 71013 San Giovanni Rotondo, Italy; Department of Pediatrics (M.W.), University of Messina, 98100 Messina, Italy; West Midlands Regional Genetics Service (T.C.), Birmingham Womens Hospital, Birmingham B60 2AY, United Kingdom; Fondazione Ospedale Maggiore Policlinico (P.B.-P.), Istituto di Ricovero e Cura a Carattere Scientifico, 20122 Milan, Italy; and Section on Women’s Health Research (L.M.N.), Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Luca Persani, M.D., Ph.D., Department of Medical Sciences, University of Milan, Laboratory of Experimental Endocrinology, Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico, Via Zucchi 18, 20095 Cusano Milanino, Italy. E-mail: luca.persani{at}unimi.it.

Context: Premature ovarian failure (POF) is a cause of female infertility characterized by primary (PA) or secondary amenorrhea (SA) and elevated gonadotropins. The pathogenesis is unknown in most cases. We recently reported two sisters with PA carrying a heterozygous mutation of BMP15 gene (locus Xp11.2), but the prevalence of BMP15 variations in the POF population is unknown.

Objective: The objective of the study was to verify the involvement of BMP15 variations in a large POF population.

Design and Subjects: Genetic screening of 166 unrelated patients with idiopathic POF (25 PA, 141 SA) and controls (group A: 95 women with menopause beyond 50 yr of age; group B: 86 women and 30 men from the general population) of Caucasian origin.

Results: Investigation revealed four heterozygous variations affecting the proregion of BMP15. The previously reported p.Y235C mutation occurred in one and three novel variants in eight patients: two missense alterations (p.R68W in one case, p.A180T in five) and one insertion (p.262insLeu) in two cases. The p.262insLeu was found in five controls of group A, thus diminishing its potential biological impact, whereas the other three variants were not present in any of the controls. All new mutations were found in SA cases.

Conclusion: We describe the significant association of heterozygous BMP15 gene variants with the POF phenotype in humans (seven of 166 patients: 4.2%; P < 0.003 vs. controls). These findings are consistent with the critical role played by BMP15 in human folliculogenesis.

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