How an Autism Gene Contributes to Infertility
Summary: FMR1, a mutation in the gene that causes Fragile X syndrome is also implicated in premature ovarian failure, resulting in infertility in women. The mutation changes the neurons that regulate reproduction in the brain and ovaries.
A study by the University of California, Riverside, has identified the biological basis of a reproductive disorder caused by the mutation of a gene. This gene mutation also causes Fragile X syndrome, a major genetic cause of intellectual disability and autism.
The researchers found that mutations in the fragile X messenger ribonucleoprotein 1 gene, or FMR1, contribute to premature ovarian failure, or POF, because of changes in neurons that regulate reproduction in the brain and ovaries. The mutation has been associated with early infertility, due to a 25-fold increased risk of POF, but the reasons were unclear.
POF is the most severe form of premature ovarian aging, which affects about 10% of women and is characterized by an early depletion of ovarian follicles and early menopause. With women delaying reproduction, the chances of infertility increase, including due to the FMR1 mutation.
“In the last two or three decades, the average age of first-time mothers in the US and Europe has increased steadily,” said Djurdjica Coss, a professor of biomedical sciences at the UCR School of Medicine, who led the research team.
“Furthermore, premature menopause causes not only early infertility, but also increased risk of cardiovascular disease and osteoporosis. Therefore, it is important to understand the reasons for these reproductive disorders and eventually find treatments. Such research could also help better counsel at-risk women about when to have a baby and how to monitor their health outcomes.
According to the Centers for Disease Control and Prevention, 19% of heterosexual couples in the US experience infertility and need assisted reproductive technology, which can be very expensive for many couples.
Coss explained that previous studies of FMR1-mediated reproductive disorders analyzed them exclusively from an endocrine perspective, meaning they studied changes in hormone levels and how the endocrine cells in the ovaries that produce them functioned.
“We took a different approach,” Coss said. “Since the FMR1 gene is highly abundant in neurons, we hypothesized that the neurons that regulate reproduction are affected by the FMR1 mutation, which in turn causes increased hormone levels.
“Indeed, we found higher stimulation of neurons in the hypothalamus that regulate reproduction as well as more neurons in the ovaries that contribute to the synthesis of ovarian hormones.”
To do the research, Coss and her team used transgenic mice that lack the FMR1 gene to mimic the condition in humans with a mutation in this gene. They first determined that this mouse model mimics what is seen in women with an FMR1 mutation. They then compared the neurons that regulate reproduction in the ovaries and brain between these mice and their normal counterparts.
They found that changes in the function of these neurons led to a faster secretion of hormones in young transgenic female mice that later stopped reproducing early. Next, they removed the ovaries from these mice to determine the effect of the FMR1 mutation only on neurons in the brain.
The researchers found that mutations in the fragile X messenger ribonucleoprotein 1 gene, or FMR1, contribute to premature ovarian failure, or POF, because of changes in neurons that regulate reproduction in the brain and ovaries. The image is in the public domain
“This allowed us to determine that these neurons in the brain, called gonadotropin-releasing hormone neurons, show changes in connectivity that affect their function,” Coss said. “Increasing the number of synapses causes them to be faster and have more pulses of hormone secretion.”
Her team also determined that the neurons that “innervate” the ovaries—the ones that supplied the ovaries with nerves—were more abundant in the transgenic mice than in their normal counterparts.
“We think the increases we see in ovarian hormone levels are due to increased ovarian innervation rather than increased hormone-producing cells,” Coss said. “The endocrine perspective supports the latter.”
Next, Coss and her team plan to investigate whether the effects of the FMR1 mutation can be alleviated by partially inhibiting the neurons in the ovary.
“We hypothesize that this may normalize ovarian hormone levels, possibly allowing for a normal reproductive lifespan,” Coss said.
Coss was joined in the study by Pedro A. Villa, Nancy M. Lainez, Carrie R. Jonak, Sarah C. Berlin and Iryna M. Ethell.
Funding: The study, published in the journal Frontiers in Endocrinology, was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health.
Related to this ASD and genetic research news
Author: Iqbal Pittalwala
Contact: Iqbal Pittalwala – UCR
Image: Image is in the public domain
Original Research: Open Access.
“Altered GnRH neuron and ovarian innervation characterize reproductive dysfunction associated with mutation of the fragile X messenger ribonucleoprotein (Fmr1) gene” by Djurdjica Coss et al. Frontiers in Endocrinology
Alteration of GnRH neuron and ovarian innervation characterizes reproductive dysfunction associated with fragile X messenger ribonucleoprotein (Fmr1) gene mutation.
Introduction: Mutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene cause Fragile X syndrome, the most common monogenic cause of intellectual disability. FMR1 mutations are also associated with reproductive disorders, such as early termination of reproductive function in females. While progress has been made in understanding the mechanisms of mental impairment, the causes of reproductive disorders are not clear. FMR1-related reproductive disorders were studied exclusively from an endocrine perspective, while the role of FMR1 in neurons controlling reproduction was not addressed.
Results: Here, we demonstrate that similar to females with FMR1 mutations, female Fmr1 null mice stop reproduction early. However, young null females exhibit larger litters, more corpora lutea in the ovaries, increased circulating inhibin, progesterone, testosterone, and gonadotropin hormones. Ovariectomy reveals hypothalamic and ovarian contributions to the increase in gonadotropins. Altered mRNA and protein levels of several synaptic molecules in the hypothalamus are identified, indicating reasons for hypothalamic dysregulation. Increased vascularization of the corpus luteum, higher sympathetic innervation of growing follicles in Fmr1 null ovaries, and a higher number of synaptic GABAA receptors on GnRH neurons, which are excitatory to GnRH neurons, contribute to increased FSH and LH, respectively. Unmodified and ovariectomized Fmr1 nulls have increased LH pulse frequency, suggesting that Fmr1 nulls display hyperactive GnRH neurons independent of ovarian responsiveness.
Conclusion: These results reveal Fmr1 function in the regulation of GnRH neuron secretion and point to the role of GnRH neurons, in addition to ovarian innervation, in the etiology of Fmr1-mediated reproductive disorders.