How a Gene That Causes Autism Also Contributes to Infertility

Researchers from the University of California, Riverside (UCR) have deciphered how a genetic mutation that causes Fragile X syndrome – a leading cause of autism – also contributes to infertility. The study, conducted in mice, is published in Frontiers in Endocrinology.

Premature ovarian failure affects women under 40

Premature ovarian failure (POF) is a condition where the ovaries do not produce normal amounts of the hormone estrogen, or release eggs regularly. It occurs in women under the age of 40 and affects approximately 10% of the population.

One of the most severe forms of premature ovarian aging, POF can impact a person’s likelihood of conceiving. As more individuals are opting to start a family later in life, researchers are working to understand the biological underpinnings of POF, so that this knowledge can support people in their plans to have a child.

“In the last two or three decades, the median age of first-time mothers in the United States and Europe has steadily increased,” says Djurdjica Coss, a professor of biomedical sciences in the UCR School of Medicine. “Moreover, premature menopause causes not only early infertility, but also increased risk of cardiovascular disease and osteoporosis. It’s important, therefore, to understand the reasons behind these reproductive disorders and eventually find treatments. Such research can also help better advise women at risk on when to have a child and how to monitor their health outcomes.”

Mutations of the Fragile X messenger ribonucleoprotein 1 gene – FMR1 – which encodes the FMR protein, are associated with early infertility and can lead to a 25-fold increased risk of developing POF. Why this association exists has remained unclear. Coss explains that previous research exploring FMR1-mediated reproductive issues has done so through an endocrine lens, i.e., studying changes in hormone levels as a result of the mutation. In the new study, her team adopted a different approach that homed in on neuronal function. “Since the FMR1 gene is highly abundant in neurons, we postulated that neurons that regulate reproduction are affected by the FMR1 mutation, which in turn causes increases in hormone levels,” she describes.

Like humans, mice lacking the FMR1 gene stop reproducing early

The research team engineered transgenic mice lacking the FMR1 gene – known as a “knock-out” mouse – to create a laboratory model that could be used to study the impact of FMR1 mutations in humans. “Since women with FMR1 mutation experience increased risk of early menopause, to begin investigating the role of the FMR protein in reproductive function, we first determined if the lack of the protein in female FMR1 knock-out mice can mimic reproductive dysfunctions observed in women with reduced levels of FMR protein due to FMR1 mutation,” the authors write in the publication.

Similar to women with FMR1 mutation, the transgenic mice experienced an early cessation of reproductive function compared to controls. “While control females continued to produce litters for at least 10 litters, the number of FMR1 knock-out females that continued to produce litters decreased after each litter, and only 5 out of 11 FMR1 knock-out females had a fourth litter, while none had an eighth litter,” the authors note.

When comparing the reproduction-regulating neurons in the brain and ovaries of the transgenic mice to control groups, the researchers found that young FMR1 knock-out mice experienced a rapid surge in hormone secretion compared to controls.

Inhibiting ovarian neurons to alleviate the impact of FMR1 mutation

Coss and colleagues extracted the transgenic mice’s ovaries to focus solely on the effect of FMR1 knock-out on the neurons present in the brain. Here, they found an increase in synaptic connectivity. “This allowed us to determine that these neurons in the brain, called gonadotropin-releasing hormone neurons, show changes in connectivity that affect how they function,” Coss explains. “The increased number of synapses cause them to be faster and have more pulses of hormone secretion.”

On a morphological level, the ovaries of the transgenic mice were found to have increased nerve innervation – i.e., a greater number of nerves supplying the ovaries – compared to control groups. “We think the increases we see in ovarian hormone levels are due to increases in ovarian innervation rather than increases in hormone-producing cells,” Coss says.

Could inhibiting neurons in the ovaries alleviate the impact of FMR1 mutation? That’s the next research question for Coss and team to address. “We anticipate this may normalize ovarian hormone levels, possibly allowing for a normal reproductive lifespan,” Coss concludes.

Reference: Villa PA, Lainez NM, Jonak CR, Berlin SC, Ethell IM, Coss D. Altered GnRH neuron and ovarian innervation characterize reproductive dysfunction linked to the Fragile X messenger ribonucleoprotein (Fmr1) gene mutation. Front Endocrinol. 2023;14. doi: 10.3389/fendo.2023.1129534.

This article is a rework of a press release issued by the University of California, Riverside. Material has been edited for length and content.