FOXL2

The FOXL2 gene provides instructions for making a protein that attaches (binds) to specific regions of DNA and helps control the activity of particular genes. On the basis of this role, the FOXL2 protein is called a transcription factor. The FOXL2 protein is active in the developing eyelids and ovaries before birth. This protein also plays a role in the maintenance of the ovaries throughout adult life. The specific function of the FOXL2 protein is unknown, but it is thought to be involved in many regulatory functions within cells.

The FOXL2 protein contains one area where a protein building block (amino acid) called alanine is repeated multiple times. This stretch of alanines is known as a polyalanine tract or poly(A) tract.

blepharophimosis, ptosis, and epicanthus inversus syndrome - caused by mutations in the FOXL2 gene

More than 130 mutations in the FOXL2 gene have been found to cause blepharophimosis, ptosis, and epicanthus inversus syndrome (also called BPES). Mutations that lead to a significantly shortened FOXL2 protein often cause BPES type I, which is characterized by eyelid malformations and premature ovarian failure. Premature ovarian failure causes a woman's menstrual periods to become less frequent and eventually stop before age 40, leading to a partial or complete inability to conceive a child (subfertility or infertility, respectively). Mutations that result in an extra long FOXL2 protein may cause BPES type II, which involves only eyelid malformations. A common mutation in people with BPES adds alanines to the polyalanine tract in the FOXL2 protein. These extra alanines cause the FOXL2 protein to be abnormally long and functionally impaired.

The majority of mutations that cause BPES occur within the FOXL2 gene; however, some disease-causing mutations occur in a neighboring region of DNA that normally regulates the activity of the FOXL2 gene, known as a regulatory region. It is estimated that about 5 percent of people with BPES have a mutation in a regulatory region outside the FOXL2 gene.

Some people with BPES have large DNA deletions that remove not only the FOXL2 gene but one or more neighboring genes. Individuals with these large DNA deletions have the signs and symptoms of BPES, but they can also have other features. The combination of additional features depends on which genes are included in the deletion, but can include an unusually small head (microcephaly), intellectual disability, heart defects, and growth delay.