Ovary gene may explain certain aspects of infertility

Harvard Medical School researchers have uncovered an ovary gene whose absence from mouse egg cells produced severe pregnancy complications. The gene, Fmn2, which produces the protein formin-2, is similar in mice and humans and offers promise for understanding embryo loss, birth defects, and infertility in women. The study appears in the December Nature Cell Biology.

“As humans we are incredibly bad at producing eggs with the normal number of chromosomes, which is the leading cause of pregnancy loss in women,” says Benjamin Leader, an HMS MD/PhD candidate, and the paper’s lead author. “The biological means for ensuring proper distribution of chromosomes to the egg has been difficult to determine.

“Our study shows that the formin-2 gene is required in order to ensure the proper distribution of chromosomes to the egg. About one percent of women suffer from recurrent pregnancy loss, which can be defined as a loss of greater than two or three pregnancies. We are now actively searching for mutations involving the formin-2 gene in women with reproductive loss and infertility,” Leader added.

Egg cells lacking Fmn2 were unable to complete the first round of reproductive cell division, known as meiosis I. The egg cell failed to correctly position a significant protein-DNA, the metaphase spindle, thereby halting the division process. The result was lack of formation of the first polar body, a new cell that signifies completion of the first meiotic division, and the daughter egg cell, which would otherwise develop into a mature egg.

Leader observed that Fmn2-deficient female mice produced embryos with three or five sets of chromosomes, a deviation that resulted in cell death. Normal mice with Fmn2 produce embryos with two sets of chromosomes. The researchers also found that healthy ovaries transplanted into Fmn2-deficient females rescued pregnancy loss, whereas transplant of Fmn2-deficient ovaries into healthy females destroyed the healthy females’ ability to produce offspring. Furthermore, examination of the experimental mice revealed a radically reduced number of embryos in Fmn2-deficient females.

This research was supported in part by the Howard Hughes Medical Institute and a Howard Hughes Medical Institute pre-doctoral fellowship grant.

Harvard Medical School has more than 5,000 full-time faculty working in eight academic departments based at the School’s Boston quadrangle or in one of 47 academic departments at 17 affiliated teaching hospitals and research institutes. Those HMS affiliated institutions include Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Cambridge Hospital, Center for Blood Research, Children’s Hospital, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children’s Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation Hospital, VA Boston Healthcare System.

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