Premature Ovarian Failure 3

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.

For a discussion of genetic heterogeneity of premature ovarian failure, see POF1 (311360).

Clinical Features

Premature ovarian failure is defined by the cessation of ovarian function under the age of 40 years and is characterized by amenorrhea, hypoestrogenism, and elevated serum gonadotropin concentrations (summary by Harris et al., 2002).

Molecular Genetics

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 (605597.0017) in a patient from New Zealand. The Slovenian patient was shown at the age of 17 years to have a small hypoplastic uterus and small ovaries with no visible follicles. The normal mother and sister of the patient did not carry this variant, but the status of the father regarding the mutation could not be determined as he was deceased. The New Zealand patient experienced menarche at age 14 years and menstruation was normal until age 36 years, when menopausal symptoms were noted. Menopause was confirmed at age 38 years by FSH (see 136530) measurement. The patient's mother was also heterozygous for this variant. Neither mutation was identified in 200 control chromosomes.

In a 26-year-old Tunisian patient 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.