Alternative titles; symbols
Other entities represented in this entry:
ORPHA: 243; DO: 0080494, 0080861;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.22 | Ovarian dysgenesis 2 | 300510 | X-linked | 3 | BMP15 | 300247 |
| Xp11.22 | Premature ovarian failure 4 | 300510 | X-linked | 3 | BMP15 | 300247 |
A number sign (#) is used with this entry because of evidence that ovarian dysgenesis-2 (ODG2) is caused by mutation in the BMP15 gene (300247) on chromosome Xp11. One such family has been reported.
Mutation in the BMP15 gene can also cause premature ovarian failure-4 (POF4).
For a discussion of genetic heterogeneity of ovarian dysgenesis, see ODG1 (233300).
For a phenotypic description and a discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360).
Hypergonadotropic ovarian failure is a heterogeneous disorder that, in the most severe forms, is a result of ovarian dysgenesis. Ovarian dysgenesis accounts for about half the cases of primary amenorrhea (Timmreck and Reindollar, 2003). Most cases are associated with major X chromosome abnormalities. Accordingly, genetic studies have identified several loci at Xq and Xp11.2-p.22.1 whose functions are relevant for ovarian development (Zinn et al., 1998; Simpson and Rajkovic, 1999; Marozzi et al., 2000).
Di Pasquale et al. (2004) reported 2 sisters with hypergonadotropic ovarian failure due to ovarian dysgenesis. The proband presented at age 23 with primary amenorrhea and modest hirsutism. She had received a diagnosis of pubertal delay at 15 years; at age 17 years she underwent appendectomy, and laparoscopic investigation allowed the visualization of streak ovaries with a small terminal crest and underdevelopment of the uterus. Her younger sister was affected with a similar menstrual defect, reporting a single episode of spotting at age 13 years. Both patients had hypoplastic gonads at ultrasound and a 46,XX karyotype. The parents were nonconsanguineous, and family history was negative for reproductive, endocrine, or mental disorders in 2 previous generations.
Ovarian Dysgenesis 2
In 2 sisters with hypergonadotropic ovarian failure due to ovarian dysgenesis, Di Pasquale et al. (2004) identified a heterozygous transition in exon 2 of the BMP15 gene resulting in a tyr235-to-cys amino acid substitution (Y235C; 300247.0001). The father was a hemizygous carrier of the mutation, whereas the mother carried only wildtype BMP15. Because the affected sisters' phenotype resembled that observed in patients with complete resistance to follicle-stimulating hormone (see ODG1, 233300), mutations in the FSHR gene (136435) were excluded in the proband. The authors also noted that the BMP15 Y235C-associated phenotype reflected the phenotype of sheep with homozygous BMP15 mutations, rather than that of heterozygous ewes (Galloway et al., 2000), suggesting that the affected sisters might carry mutations in other genes involved in ovarian function. Screening of the GDF9 gene (601918) did not reveal any mutations, and the authors concluded that the different modes of inheritance in humans and sheep might be a result of species diversity or the peculiar nature and location of the human mutation.
Premature Ovarian Failure 4
Dixit et al. (2006) sequenced the BMP15 gene in 133 Indian women with gonadotropin-confirmed premature ovarian failure (POF), 60 with primary amenorrhea, 9 with secondary amenorrhea, and 197 controls and identified 11 missense mutations (see, e.g., 300247.0002-300247.0004) in 19 patients with POF or primary amenorrhea but not in controls. Three frequent variants 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.
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 (see, e.g., 300247.0005 and 300247.0006) in 29 women that were not found in 216 controls. They 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.
Di Pasquale et al. (2006) sequenced the BMP15 gene in 166 unrelated Caucasian women with idiopathic POF and identified 2 novel missense mutations in 6 patients, all of whom had secondary amenorrhea: an R68W substitution (300247.0005) was detected in 1 patient, and an A180T substitution (300247.0006) in 5 patients. Neither variant was found in 211 controls. The authors stated that analysis of 14 African American, 6 Asian, and 4 Hispanic women with POF revealed 2 additional missense variants. Including their previously reported proband (Di Pasquale et al., 2004), Di Pasquale et al. (2006) calculated a significant association between heterozygous BMP15 variants and the POF phenotype (7/166 patients: 4.2%; p less than 0.003 vs controls).
Di Pasquale, E., Beck-Peccoz, P., Persani, L. Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. Am. J. Hum. Genet. 75: 106-111, 2004. [PubMed: 15136966] [Full Text: https://doi.org/10.1086/422103]
Di Pasquale, E., Rossetti, R., Marozzi, A., Bodega, B., Borgato, S., Cavallo, L., Einaudi, S., Radetti, G., Russo, G., Sacco, M., Wasniewska, M., Cole, T., Beck-Peccoz, P., Nelson, L. M., Persani, L. Identification of new variants of human BMP15 gene in a large cohort of women with premature ovarian failure. J. Clin. Endocr. Metab. 91: 1976-1979, 2006. [PubMed: 16464940] [Full Text: https://doi.org/10.1210/jc.2005-2650]
Dixit, H., Rao, L. K., Padmalatha, V. V., Kanakavalli, M., Deenadayal, M., Gupta, N., Chakrabarty, B., Singh, L. Missense mutations in the BMP15 gene are associated with ovarian failure. Hum. Genet. 119: 408-415, 2006. [PubMed: 16508750] [Full Text: https://doi.org/10.1007/s00439-006-0150-0]
Galloway, S. M., McNatty, K. P., Cambridge, L. M., Laitinen, M. P. E., Juengel, J. L., Jokiranta, T. S., McLaren, R. J., Luiro, K., Dodds, K. G., Montgomery, G. W., Beattie, A. E., Davis, G. H., Ritvos, O. Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner. Nature Genet. 25: 279-283, 2000. [PubMed: 10888873] [Full Text: https://doi.org/10.1038/77033]
Marozzi, A., Manfredini, E., Tibiletti, M. G., Furlan, D., Villa, N., Vegetti, W., Crosignani, P. G., Ginelli, E., Meneveri, R., Dalpra, L. Molecular definition of Xq common-deleted region in patients affected by premature ovarian failure. Hum. Genet. 107: 304-311, 2000. [PubMed: 11129329] [Full Text: https://doi.org/10.1007/s004390000364]
Rossetti, R., Di Pasquale, E., Marozzi, A., Bione, S., Toniolo, D., Grammatico, P., Nelson, L. M., Beck-Peccoz, P., Persani, L. BMP15 mutations associated with primary ovarian insufficiency cause a defective production of bioactive protein. Hum. Mutat. 30: 804-810, 2009. [PubMed: 19263482] [Full Text: https://doi.org/10.1002/humu.20961]
Simpson, J. L., Rajkovic, A. Ovarian differentiation and gonadal failure. Am. J. Med. Genet. 89: 186-200, 1999. [PubMed: 10727994] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19991229)89:4<186::aid-ajmg3>3.0.co;2-5]
Timmreck, L. S., Reindollar, R. H. Contemporary issues in primary amenorrhea. Obstet. Gynec. Clin. North Am. 30: 287-302, 2003. [PubMed: 12836721] [Full Text: https://doi.org/10.1016/s0889-8545(03)00027-5]
Zinn, A. R., Tonk, V. S., Chen, Z., Flejter, W. L., Gardner, H. A., Guerra, R., Kushner, H., Schwartz, S., Sybert, V. P., Van Dyke, D. L., Ross, J. L. Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1. Am. J. Hum. Genet. 63: 1757-1766, 1998. [PubMed: 9837829] [Full Text: https://doi.org/10.1086/302152]