Alternative titles; symbols
HGNC Approved Gene Symbol: BMP15
Cytogenetic location: Xp11.22 Genomic coordinates (GRCh38): X:50,910,735-50,916,641 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.22 | Ovarian dysgenesis 2 | 300510 | X-linked | 3 |
| Premature ovarian failure 4 | 300510 | X-linked | 3 |
The bone morphogenetic protein (BMP) family is part of the transforming growth factor-beta superfamily (see TGFB1, 190180), which includes large families of growth and differentiation factors. These proteins are synthesized as prepropeptides, cleaved, and then processed into dimeric proteins. With few exceptions, members of the TGFB superfamily are defined by 7 spatially conserved cysteine residues. By use of degenerative oligonucleotides on the conserved amino acids of the BMP/Vg1/DPP subgroup of the TGFB superfamily, Dube et al. (1998) identified an additional member of BMP family, BMP15, in both mouse and human. The 392-amino acid prepropeptides exhibit an overall amino acid identity of 63%, and both have 5 potential N-linked glycosylation sites, of which 3 are spatially conserved between the species. By Northern blot analysis, Dube et al. (1998) showed that mouse Bmp15 is expressed only in ovary. In situ hybridization demonstrated that Bmp15 is expressed exclusively in the oocyte soon after primordial follicles are recruited, and that expression is maintained until after ovulation. The human and mouse proteins contain 6 of the 7 conserved cysteine residues; the cysteine essential for interchain disulfide bond formation is missing. This cysteine residue is also missing in the closest relative of Bmp15, Gdf9 (601908), an oocyte-specific growth factor that is required for folliculogenesis and fertility. The spatial-temporal pattern of Bmp15 and Gdf9 are identical. Dube et al. (1998) suggested that BMP15 may thus be involved in oocyte maturation and follicular development as a homodimer or by forming heterodimers with Gdf9.
Aaltonen et al. (1999) determined the localization of the GDF9 mRNA and protein during human folliculogenesis by in situ hybridization and immunohistochemical analyses and compared it with that of GDF9B. GDF9 transcripts were not detected in primordial follicles but were abundantly expressed in primary follicles in frozen sections of ovarian cortical tissue material obtained at laparoscopic surgery. Human GDF9B transcripts could be detected only in the gonads by RT-PCR analysis, and in situ hybridization studies indicated that GDF9B is not expressed in small primary follicles but rather in the oocytes of late primary follicles. The authors concluded that (1) both GDF9 mRNA and protein are abundantly expressed in oocytes of primary follicles in human ovary, suggesting that the GDF9 transcript is translated at this early stage of folliculogenesis; (2) human GDF9B is specifically expressed in gonads at low levels; (3) expression of GDF9 mRNA begins slightly earlier than that of GDF9B in human oocytes during follicular development; and (4) the results are consistent with the suggestion that GDF9 and GDF9B may regulate human folliculogenesis in a manner specific to the ovary.
Using in situ hybridization and immunohistochemical analysis, Otsuka et al. (2000) demonstrated selective and increasing expression of BMP15 in oocytes throughout follicular development. Immunoblot analysis detected 16- and 50-kD proteins. Functional analysis showed that the addition of BMP15 to rat granulosa cells increased proliferation and DNA synthesis, which was unaffected by FSH (see 136530). BMP15 produced a marked decrease in FSH-induced progesterone production but had no effect on FSH-stimulated estradiol production, suggesting that BMP15 is a selective modulator of FSH function.
Dube et al. (1998) determined that in both mouse and human, the BMP15 protein is encoded by 2 exons; the first exon encodes the 17-amino acid signal peptide and the first portion of the propeptide region, and the second exon encodes the remainder of the propeptide region and the entire predicted 125-amino acid mature domain.
By FISH, Dube et al. (1998) mapped the human BMP15 gene to Xp11.2. Aaltonen et al. (1999) confirmed this localization using FISH. By use of an interspecific backcross panel, Dube et al. (1998) mapped the mouse Bmp15 gene to the centromere of the X chromosome, a region that shows homology of synteny to human Xp11.
Ovarian Dysgenesis 2
Di Pasquale et al. (2004) described 2 sisters with a normal karyotype who were affected with hypergonadotropic ovarian failure due to ovarian dysgenesis (ODG2; 300510). A heterozygous nonconservative substitution in the propeptide region of BMT15 (Y235C; 300247.0001) was identified in both sisters. The mutation was inherited from the father. Mutant BMP15 appeared to be processed abnormally, was associated with reduced granulosa cell growth, and antagonized the stimulatory activity of wildtype protein on granulosa cell proliferation. This family represented an exceptional example of X-linked human disease exclusively affecting heterozygous females who inherited the genetic alteration from the unaffected father.
Premature Ovarian Failure 4
Dixit et al. (2006) sequenced the BMP15 gene in 133 Indian women with gonadotropin-confirmed premature ovarian failure (see POF4, 300510), 60 with primary amenorrhea, 9 with secondary amenorrhea, and 197 controls and identified 11 missense mutations that were found only in cases of premature ovarian failure or primary amenorrhea (see, e.g., 300247.0002-300247.0004). Three frequent variants (-9C-G, rs3810682; 308A-G; and 852C-T, rs17003221) were chosen for haplotyping, and the so-called GGC haplotype was found to be significantly associated with ovarian failure (p = 0.0075). Dixit et al. (2006) concluded that the BMP15 gene is highly associated with the etiology of ovarian failure.
In a population of 166 unrelated patients with idiopathic premature ovarian failure (POF) and controls of Caucasian origin, Di Pasquale et al. (2006) found 2 novel missense alterations in 6 patients. An R68W substitution (300247.0005) was found in 1 case, and an A180T substitution (300247.0006) in 5. Neither of these variants were found in any control. These novel mutations were found in cases with secondary amenorrhea. The authors described the significant association of heterozygous BMP15 gene variants with the POF phenotype (7/166 patients: 4.2%; P less than 0.003 vs controls).
Rossetti et al. (2009) screened 300 unrelated Caucasian women with idiopathic overt primary ovarian insufficiency (POI), including 45 women with primary amenorrhea and 255 with secondary amenorrhea. The authors identified 5 heterozygous BMP15 missense variants in 29 women that were not found in 216 controls. In vitro studies showed that with 3 of the missense variants, including R68W, there was a marked reduction in mature protein secreted, whereas with the other 2 variants, including A180T, the secretion was similar to wildtype; luciferase reporter assay confirmed larger reductions in activity with the first 3 variants and conserved activity or a slight decrease with the other 2 variants. The authors observed no clear-cut genotype/phenotype correlations with the BMP15 mutations, noting that the most deleterious mutation they studied was found in women with onset of POI at 20 and 30 years of age, whereas POI occurred before 20 years of age in carriers of 2 less deleterious mutations. Rossetti et al. (2009) suggested that BMP15 variations may predispose to POI and contribute in association with other alterations to generate the ovarian defect.
Multiple ovulations are uncommon in humans, cattle, and many breeds of sheep. Pituitary gonadotropins and ovarian factors precisely regulate follicular development so that, normally, only 1 follicle is selected to ovulate. Inverdale sheep, however, carry a naturally occurring X-linked mutation that causes increased ovulation rate and twin and triplet births in heterozygotes, but primary ovarian failure in homozygotes. Germ cell development, formation of the follicle, and the earliest stages of follicular growth are normal in homozygous mutant sheep, but follicular development beyond the primary stage is impaired. A second family of sheep unrelated to the Inverdale, the Hanna sheep, was found to have the same X-linked phenotype. Crossing the 2 animals produced heterozygous, doubly mutant, infertile females phenotypically indistinguishable from homozygous Inverdale females. Galloway et al. (2000) reported that the mutant locus maps to a chromosomal region syntenic to human Xp11.4-p11.2, which contains the BMP15 gene. Galloway et al. (2000) showed that independent germline point mutations exist in Inverdale and in Hanna sheep. These findings established that BMP15 is essential for female fertility and that natural mutations in an ovary-derived factor can cause both increased ovulation rate and infertility phenotypes in a dosage-sensitive manner. Ovarian dysgenesis associated with X-chromosomal defects is well known, and premature ovarian failure occurs in X0 mice and humans (Turner syndrome). Although several X-linked genes have been proposed as candidates for the infertility effects in these disorders, the mechanisms remained obscure. The findings of Galloway et al. (2000) raised the possibility that mutations in BMP15 may be one of the mechanisms involved.
Hashimoto et al. (2005) compared the molecular characteristics of Bmp15 of polyovulatory mice with those of BMP15 of monoovulatory humans. They determined that the proregion of mouse Bmp15 resists cleavage, resulting in defects in the production of the mature mouse protein. A chimeric protein containing the mouse proregion fused to the mature human BMP15 sequence was also not processed into the mature secreted protein in transfected cells. Hashimoto et al. (2005) concluded that defects in the production of mouse Bmp15 are associated with the high ovulation quota and litter size observed in mice.
Heterozygous and homozygous missense mutations in Bmp15 and Gdf9 (601918) cause elevated fertility and infertility, respectively, in ewes. Using recombinant human BMP15 and GDF9 with mutations corresponding to those identified in sheep, Liao et al. (2004) found that the 2 BMP15 point mutations decreased BMP15 and GDF9 secretion. The GDF9 point mutation had little effect on GDF9 function on its own, but augmented the effects of the BMP15 mutations on secretion of BMP15 and GDF9.
Di Pasquale et al. (2004) reported an Italian family in which 2 sisters had hypergonadotropic ovarian failure due to ovarian dysgenesis (ODG2; 300510). At 23 years of age, the proband presented with primary amenorrhea and modest hirsutism. During appendectomy at the age of 17 years, laparoscopy showed streak ovaries with underdeveloped uterus. Her younger sister was affected with a similar menstrual defect and had reported a single episode of spotting at 13 years. The phenotype of these patients was similar to that observed in patients with complete resistance to follicle-stimulating hormone (see 233300). The heterozygous mutation in BMP15 in the sisters was an A-to-G transition at basepair 704 of the BMP15 gene that resulted in a tyr235-to-cys (Y235C) amino acid substitution. The father was a hemizygous carrier, whereas the mother had a wildtype BMP15 coding sequence. The mutation was found in the second exon, in a highly conserved part of the BMP15 gene encoding the propeptide region. The mutation was not found in 210 alleles from 120 ethnically matched controls. Di Pasquale et al. (2004) demonstrated a dominant-negative effect of the mutated protein upon the wildtype, and predicted the mutation to cause relevant modifications in the conformation of the BMP15 precursor, possibly leading to altered processing and impaired activation of latent forms or to abnormal dimerization.
In 5 Indian women with POF4 (see 300510), 2 of whom had primary amenorrhea, Dixit et al. (2006) identified heterozygosity for a 226C-T transition in exon 1 of the BMP15 gene, resulting in an arg76-to-cys (R76C) substitution. The ovaries of 1 woman with POF were not visualized, and another had streak ovaries; 1 of the patients with primary amenorrhea had mullerian agenesis, bilateral pelvic kidneys, and deficient secondary sexual characteristics.
In 3 Indian women with POF4 (see 300510), 2 of whom had primary amenorrhea, Dixit et al. (2006) identified heterozygosity for a 538G-A transition in exon 2 of the BMP15 gene, resulting in an ala180-to-thr (A180T) substitution. One of the patients with primary amenorrhea was also noted to have short stature.
In a 28-year-old Indian woman with POF4 (see 300510), Dixit et al. (2006) identified homozygosity for a 631C-T transition in exon 2 of the BMP15 gene, resulting in a glu211-to-ter (E211X) substitution. The patient had severely hypoplastic ovaries with complete infertility, never attained menarche, and expressed high gonadotropin levels. She also had facial paralysis with a skewed lower mandible; Dixit et al. (2006) suggested that this might be indicative of a developmental role for the BMP15 gene.
In a 16-year-old patient with premature ovarian failure (POF4; see 300510) presenting as secondary amenorrhea, Di Pasquale et al. (2006) found a heterozygous C-to-T transition at nucleotide 202 of the BMP15 gene that resulted in an arg-to-trp substitution at codon 68 (R68W). The mutation was predicted to cause a major alteration in precursor structure, with a basic, positively charged arginine being replaced by an aromatic, neutral tryptophan. The patient's mother, grandmother, and 6 maternal cousins experienced early menopause, before 28 years of age.
Rossetti et al. (2009) identified heterozygosity for the R68W mutation in the BMP15 gene in Caucasian patients with primary ovarian insufficiency. Transfection studies in HEK293 cells showed a marked reduction of mature protein secreted, estimated at 8-fold lower compared to wildtype. Luciferase reporter assay showed a 25 to 33% reduction in activity compared to wildtype.
In 5 patients with premature ovarian failure (POF4; see 300510) presenting as secondary amenorrhea, Di Pasquale et al. (2006) found a heterozygous G-to-A transition at nucleotide 538 of the BMP15 gene that resulted in an ala180-to thr (A180T) substitution. The A180T variation led to the introduction of a polar residue susceptible to change the charge of the region. Onset of ovarian failure ranged from ages 21 to 29 years and was preceded by a period of menstrual irregularity.
Rossetti et al. (2009) identified heterozygosity for the A180T mutation in the BMP15 gene in Caucasian patients with primary ovarian insufficiency. Transfection studies in HEK293 cells with the A180T variant showed secretion of mature protein in an amount similar to wildtype, and a luciferase reporter assay showed conserved stimulatory activity.
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