Ovarian Dysgenesis 2

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.

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).

Description

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).

Clinical Features

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.

Molecular Genetics

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 (300247.0001). The father was a hemizygous carrier of the mutation, whereas the mother carried only wildtype BMP15.

The phenotype of the patients studied by Di Pasquale et al. (2004) resembled that observed in patients with complete resistance to follicle-stimulating hormone (see 233300). Di Pasquale et al. (2004) excluded mutations in the FSHR gene (136435) in the proband. The mutation in the BMP15 gene found in the patients (300247.0001) was associated with prepubertal onset of hypergonadotropic ovarian failure characterized by primary amenorrhea and ovarian hypoplasia. These manifestations reflect the phenotype of sheep with homozygous mutations, rather than that of heterozygous ewes (Galloway et al., 2000). The possibility that the affected sisters carried mutations in other genes involved in ovarian function may explain such a discrepancy. Nevertheless, mutations in the GDF9 (601918) and FSHR genes were not detected, possibly suggesting that the different modes of inheritance in humans and sheep may be a result of species diversity or the peculiar nature and location of the human mutation.

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).