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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.

	Abstract

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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.

	Introduction

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PREMATURE OVARIAN FAILURE (POF, Online Mendelian Inheritance in Man 311360) is a disorder associated with female infertility affecting 1–2% of women under 40 yr of age (1, 2). It is a heterogeneous disease clinically characterized by primary amenorrhea (PA) in major defects with prepubertal onset or secondary amenorrhea (SA) in women with postpubertal onset (1, 2, 3). The diagnosis is supported by biochemical findings showing the association of elevated gonadotropins and low estrogen levels.

Several mechanisms may be involved in POF pathogenesis, but the genetic contribution is a significant etiological component (1, 4). Genetic studies have identified several loci at Xq22, Xq26-q28, and Xp11.2-p22.1 whose disruption has been associated with POF (4, 5, 6). Furthermore, alterations in autosomal genes, such as FSHR, LHR, FOXL2, INHA, GALT, are rarely associated with POF (1, 7), and the pathogenesis remains most frequently unsolved (1, 8).

Recently attention has been focused on members of TGFß superfamily and their potential role as local modulators of ovarian function (9, 10). Among these, growth differentiation factor-9 (GDF9) and bone morphogenetic protein-15 (BMP15) originate from the oocyte and have been shown to be critical regulators of ovulation rates and litter size and to be required for the progression of early folliculogenesis in rodents and sheep. Targeted deletion of Gdf9 or Bmp15 gene leads to female infertility or subfertility in mice (9, 11). Natural mutations in sheep cause increased ovulation rate in heterozygotes or early block of folliculogenesis and sterility in homozygous or compound heterozygous animals (9, 10, 12, 13). These genes encode prepro-proteins composed of signal peptide, proregion and mature peptide. Proteolytic cleavage of propeptides and formation of mature homo- or heterodimers represent critical steps for the bioactivity of these factors (9, 10, 11, 12, 13, 14).

Based on evidence in animal models, GDF9 and BMP15 can be considered candidate genes in POF. Indeed, we very recently identified the first mutation in BMP15 gene (p.Y235C) in two sisters affected with PA due to ovarian dysgenesis (15). Both sisters were heterozygous for this mutation that was inherited from the hemizygous father, representing an unusual case of X-linked disease in which the affected women inherit the alteration from a male carrier. The reported mutation was an A to G transition at position 704 of the BMP15 gene, leading to a nonconservative substitution in the proregion that was associated with a defective processing of the mutant precursor and altered biological activity (15).

Because the prevalence of BMP15 gene alterations is still undefined among POF patients, here we present the results of BMP15 genetic analysis in a large series of women with idiopathic POF.

	Subjects and Methods

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Subjects

A total of 166 unrelated Caucasian women (79 American, 87 European) affected by idiopathic POF (aged 12–39 yr) were collected from all the clinical centers participating in this study. Inclusion criteria were represented by the presence of amenorrhea for a period more than 6 months before the age of 40 yr associated with two distinct determinations of FSH concentration in the postmenopausal range (8). The association with complex or other endocrine diseases was excluded by medical history, physical examination, and biochemical determination. The selected POF population included 25 patients with PA, 15 sporadic, and 10 probands of familial cases and 141 women with SA (age at POF: 13–39; mean ± SD: 28 ± 8; median: 29 yr), 74 sporadic, and 67 probands of familial cases. All selected patients had a normal karyotype analysis based on high-resolution banding technique.

Genetic investigation was extended to two control groups of Caucasian subjects. Group A was represented by 95 women with physiological menopause beyond 50 yr of age. Control group B included 86 women and 30 men from the general population.

Institutional ethical committees approved the study, and informed consent for blood sampling and genetic investigations were obtained from all participants.

Genetic analysis

The entire coding sequence and intron-exon junctions of BMP15 gene were analyzed in all participants. Patients’ samples were screened by denaturant HPLC (dHPLC) of PCR-amplified fragments on an automatic instrument (WAVE apparatus, Transgenomics Inc., San Jose, CA). BMP15 sequence was divided into five fragments, two for the amplification of exon 1 and three for exon 2. Primer sequences and PCR conditions are available upon request. Each PCR sample from the POF patients was mixed 5:1 with a product obtained from a wild-type DNA. The acetonitrile gradient and temperatures for dHPLC analysis were obtained using an algorithm (WAVE Maker; Transgenomics). The appearance of additional peaks was interpreted as indicative of a mismatch in the analyzed PCR fragment. In these cases, a new PCR product was sequenced in both directions using an automatic genetic analyzer as previously reported (15). Control samples were directly sequenced. The significance of allelic distribution in the POF and control groups was determined by Fisher’s exact test.

	Results

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Genetic analysis revealed the presence of four variants of BMP15 gene in nine of 166 POF patients. The mutation p.Y235C was found in the previously reported proband (patient 118 in Table 1), whereas three novel BMP15 variants were present in eight POF women. All novel alterations are nonconservative and include two missense substitutions (c.202C > T p.R68W; c.538G > A p.A180T) and one insertion of three nucleotides (c.788insTCT p.262insLeu) (Fig. 1). The clinical data of the nine POF patients who were heterozygous carriers of BMP15 variants are reported in Table 1. In particular, p.A180T variant was found in five patients (3.0%; P < 0.02 vs. 0/392 control alleles) and p.R68W in one, all presenting with SA. The p.ins262Leu variant was found in two patients, one SA and one PA. All variants were located in the proregion. The age of POF onset in SA cases with BMP15 variants was early (range 15–29 yr) (Table 1), but biochemical data of these patients did not differ from those of the others.

View larger version (30K): [in this window] [in a new window]   FIG. 1. The novel BMP15 sequence variations are illustrated. The dHPLC results are represented in left panels and the corresponding electropherograms of the sequence are shown in the right panels. In these cases, the absence of additional variations was confirmed by direct automatic sequencing of the entire BMP15 coding sequence.

Finally, genetic screening confirmed the presence of two conflicts in the sequence of BMP15 (GenBank no. AF082349 and AJ132405) (16, 17). One substitution is located in the 5' untranslated region (g.-9G > C) and was identified in 86.7% of patients and in 61.0 or 71.6% of controls from group A or B, respectively. The other substitution localizes in exon 1 (c.308G > A) leading to the variation p.S103N. This change was present in 6.7% of the POF patients and 9.5 or 8.4% of the controls from group A or B, respectively.

	Discussion

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The possible involvement of BMP15 in POF pathogenesis was supported by evidences in animal models (9, 10, 11, 12, 13). Takebayashi et al. (18) could not find variations in this gene, probably due to the restricted number of analyzed samples (n = 15). Recently we (15) reported the first mutation of BMP15 gene in two sisters with ovarian dysgenesis. This study disclosed the major role of BMP15 in the progression of early folliculogenesis also in humans (14). We therefore decided to verify the prevalence of BMP15 gene alterations among the POF populations. Samples from different centers were collected, and a large cohort of unrelated patients with PA or SA was analyzed. These analyses revealed the presence of four different variants in nine POF heterozygous patients.

All variants are located in the part of the gene encoding the proregion, which is highly conserved across species and has a critical role in correct precursor processing, dimerization, and secretion of mature protein (9, 11, 14, 19). The p.ins262Leu is located close to the endopeptidase consensus sequence (RRXR) for propeptide cleavage and was detected in one PA and one SA case with a very early onset. Nevertheless, this insertion was observed in 5% of the control women with menopause beyond 50 yr and is also present in the wild-type sequence of several other mammals, thus reducing the possibility of a relevant biological impact in POF pathogenesis. All the other variants were not found among 392 control alleles. These findings are good arguments in favor of a possible effect of these variations in BMP15 precursor processing. This possibility was indeed supported by the functional studies reported in the case of the previously reported p.Y235C mutation (15).

The introduction of a cysteine could lead to aberrant dimerization and produce major functional effects in folliculogenesis consistent with the report of this mutation in 46, XX women with ovarian dysgenesis. Two novel missense variations were instead detected among the SA cases, which may predict a minor disruption of oocyte-growth factor processing and folliculogenesis progression by these substitutions. Major alteration in precursor structure is expected by R68W variation with a basic, positively charged arginine replacing an aromatic, neutral tryptophan. Consistent with this expectation, this mutation was detected in a patient who underwent POF at 16 yr after only one spontaneous menstruation. She had a familial form of POF, with her mother, grand-mother, and six maternal cousins who experienced early menopause before 28 yr of age. The A180T variation leads to the introduction of a polar residue susceptible to change the charge of the region. This variant was detected in five SA patients and is significantly associated with POF. The onset age ranged 21–29 yr and was preceded by a period of menstrual irregularity. None of these five cases was familial, but patient 92 had a 30-yr-old sister with hot flashes at the time of sampling. We also had the opportunity to study a small number of POF women with SA of other ethnicity (14 African-Americans, six Asians, four Hispanics). Two additional missense variants, p.S5R and p.L148P, were detected among the African-Americans (POF onset: 34 and 20 yr) (data not shown).

Functional studies are required to definitively support the biological impact of novel alterations, but the specific location in the proregion and early POF onset in vivo as with the originally described mutation is an argument in favor of a similar mechanism in POF pathogenesis. A recent study (19) reinforced the role of BMP15 proregion in the posttranslational processing and proposed its involvement in the generation of species-specific differences in ovulation quota among mammals, suggesting that alterations in BMP15 proprotein may have direct consequences in female reproductive physiology. Dixit et al. (20) recently reported the significant association of GDF9 gene variants, including two missense mutations affecting the proregion, with POF phenotype. This finding represents an additional support to the potential involvement of alterations in oocyte growth/differentiation factor pathway in human ovarian failure.

In conclusion, BMP15 gene variants are significantly more prevalent among Caucasian women with POF, supporting the view that BMP15 plays a critical role in early human folliculogenesis. Thus BMP15 represents a candidate for POF, either associated with primary or secondary amenorrhea. Because BMP15 gene maps within the Xp locus linked to POF (5), the present data support the concept that BMP15 represents one of the genes whose haploinsufficiency significantly contributes to ovarian dysgenesis in Turner syndrome.

	Footnotes

 
This work was partially supported by the Italian Ministry of Education, University and Research (PRIN 2004) and Research Funds of Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Auxologico Italiano (Project GENIPOF, 05C501, to L.P.) as well as the Intramural Research Program, National Institutes of Health, Bethesda, Maryland. L.M.N. is a Commissioned Officer in the United States Public Health Service.

Disclosure Summary: E.D.P., R.R., A.M., B.B., S.B., S.E., G.Ra., G.Ru., M.S., M.W., T.C., P.B.-P., L.M.N., and L.P. have nothing to declare. L.C. was a consultant of Eli Lilly and received lecture fees from Aventis.

First Published Online February 7, 2006

Abbreviations: BMP15, Bone morphogenetic protein-15; dHPLC, denaturant HPLC; GDF9, growth differentiation factor-9; PA, primary amenorrhea; POF, premature ovarian failure; SA, secondary amenorrhea.

Received December 6, 2005.

Accepted February 1, 2006.

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