A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency

About one in 100 women under the age of 40 experience a condition known as primary ovarian insufficiency, which is sometimes known as premature menopause. Women with this condition may have fewer egg cells and are usually infertile. Women with primary ovarian insufficiency are also more at risk of other diseases, including the bone disorder osteoporosis and cardiovascular diseases. The condition is thought to have a genetic basis in part, although so far its causes are largely unknown. Fouquet, Pawlikowska et al. looked at all the genes in genomes of three women in one Finnish family: two sisters and their mother. Both of the sisters had primary ovarian insufficiency, but were otherwise healthy. Their mother did not have the condition. The genetic analysis identified a mutation in a gene called FANCM, which is involved in the cell’s repair response to DNA damage and has recently been linked to breast cancer. This gene is mostly active in egg cells within the ovary. The sisters’ protein made from this mutated copy of the gene was cut short compared with the protein produced by the mother’s FANCM gene. Due to the mutation, the sisters were more sensitive to chemicals that can damage the DNA, effectively making their genome less stable. The affected sisters also had higher levels of abnormalities in the chromosomes compared with their unaffected mother. Fouquet, Pawlikowska et al. then inserted a healthy version of the FANCM gene into the sisters’ cells. This reversed the sensitivity of the sisters’ cells to DNA-damaging chemicals. The findings confirm a genetic link between primary ovarian insufficiency and genes responsible for DNA repair. Mutations in these genes can also make people more at risk of certain cancers. The findings point towards offering some women who have primary ovarian insufficiency in-depth genetic counselling with a long-term follow-up, when alterations of cancer-susceptibility genes are responsible for their condition.