DO: 0080860;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q22.3 | Premature ovarian failure 3 | 608996 | Autosomal dominant | 3 | FOXL2 | 605597 |
A number sign (#) is used with this entry because of evidence that premature ovarian failure-3 (POF3) is caused by heterozygous mutation in the FOXL2 gene (605597) on chromosome 3q22.
Premature ovarian failure-3 (POF3) is characterized by the cessation of ovarian function before the age of 40 years, with amenorrhea, hypoestrogenism, and elevated serum gonadotropin concentrations (summary by Harris et al., 2002).
For a discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360).
Harris et al. (2002) described 2 women with premature ovarian failure and mutation in the FOXL2 gene. A Slovenian patient was shown at the age of 17 years to have a small hypoplastic uterus and small ovaries with no visible follicles. A patient from New Zealand experienced menarche at age 14 years and had normal menstruation until age 36 years, when menopausal symptoms were noted. Menopause was confirmed at age 38 years by measurement of follicle stimulation hormone (FSH; see 136530).
Laissue et al. (2009) reported a 27-year-old Tunisian woman with premature ovarian failure and mutation in the FOXL2 gene. She had a normal pubertal development and a 46,XX karyotype. Pelvic and ultrasound examination showed normal uterus and ovaries with several small follicles. She had FSH, luteinizing hormone (LH; see 152780), and 17-beta-estradiol (E2) within the normal menopausal range.
In 70 patients from New Zealand and Slovenia with premature ovarian failure, defined as cessation of menses for 6 or more months before the age of 40 years, Harris et al. (2002) screened the FOXL2 gene (605597) for mutations based on the finding that FOXL2 is mutated in patients with blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES; 110100), some of whom experience POF. They found 2 heterozygous mutations, a 30-bp deletion in the FOXL2 polyalanine tract in a Slovenian patient (605597.0016) and a tyr258-to-asn substitution (Y258N; 605597.0017) in a patient from New Zealand. The normal mother and sister of the Slovenian patient did not carry the mutation, but the status of the father regarding the mutation could not be determined as he was deceased. The mother of the New Zealand patient was heterozygous for the mutation. Neither mutation was identified in 200 control chromosomes.
In a 27-year-old Tunisian woman with nonsyndromic premature ovarian failure, Laissue et al. (2009) identified a heterozygous mutation in the FOXL2 gene (G187D; 605597.0019). Although the transactivation capacity of FOXL2-G187D on 2 reporter promoters, including 1 that may be relevant to the ovary, was significantly lower than that of wildtype FOXL2, the mutant was able to strongly activate a reporter construct driven by the OSR2 (611297) promoter, believed to be a crucial target of FOXL2 in the craniofacial region. Laissue et al. (2009) noted that this is compatible with the absence of BPES in this patient.
Harris, S. E., Chand, A. L., Winship, I. M., Gersak, K., Aittomaki, K., Shelling, A. N. Identification of novel mutations in FOXL2 associated with premature ovarian failure. Molec. Hum. Reprod. 8: 729-733, 2002. [PubMed: 12149404] [Full Text: https://doi.org/10.1093/molehr/8.8.729]
Laissue, P., Lakhal, B., Benayoun, B. A., Dipietromaria, A., Braham, R., Elghezal, H., Philibert, P., Saad, A., Sultan, C., Fellous, M., Veitia, R. A. Functional evidence implicating FOXL2 in nonsyndromic premature ovarian failure and in the regulation of the transcription factor OSR2. J. Med. Genet. 46: 455-457, 2009. [PubMed: 19429596] [Full Text: https://doi.org/10.1136/jmg.2008.065086]