Corrine Welt, MD, professor of internal medicine at University of Utah Health, has spent the past 20 years helping women with infertility. Despite many medical advances, primary ovarian insufficiency is the one form of infertility that lacks any treatment options, but Welt believes an answer may lie in the scores of genetic data housed in the Utah Population Database (UPDB).
While most women experience menopause around 51 years of age, women with primary ovarian insufficiency go through menopause before the age of 40, with some going through the life-altering event as early as in their teens. This rare disorder affects less than one percent of women, but the results are devastating.
“The diagnosis can be a shock, because women learn they are no longer fertile at a time when they may just be beginning to think about having children,” explains Welt. In addition, these women are at risk for serious post-menopausal conditions, like heart disease, stroke, and osteoporosis, at an earlier age.
Because primary ovarian insufficiency is an inherited disorder, Welt believes that families are the key to understanding what causes it. It is easier to find a gene mutation that is shared by multiple affected family members.
Welt and her research team focused their study on one family with three generations of women affected by ovarian failure. The grandmother, mother, and a sister experienced menopause in their mid-30s, while the daughter experienced menopause at age 16.
Welt and her research team conducted whole genome sequencing on the four women.
The team compared the family’s genomic sequences to genetic information obtained from 96 unaffected patients included in UPDB, as well as 96 women with primary ovarian insufficiency, but no family history.
To find rare genetic variants, the investigators sifted through the vast reams of data using three different software technologies including pVAAST and VAAST, developed at the USTAR Center for Genetic Discovery at the University of Utah.
A mutation in one gene rose to the surface in all of the results ¾ POLR2C.
“POLR2C has a mutation that is very rare but shared among all members of this family,” said Welt.
POLR2C is a gene that codes for a large section of an important enzyme that is necessary for building proteins that allow the body to function properly.
Welt spoke to experts at the University of Utah who found evidence that the impact of this gene mutation affects yeast cells that divide rapidly. She was able to show the same in a human cell line. She hypothesized that it could also affect germ cells that must divide rapidly in humans.
“As germ cells divide, they form a life complement of oocytes [immature egg cells] by the time the fetus is 12-weeks of age,” explained Welt. This mutation may cause fewer oocytes to form in the fetus. When the reduced number of oocytes die off, the women may experience premature menopause. She and her research team will carry out additional studies to validate the hypothesis.
The mutated POLR2C gene was not found in any of the control patients obtained from UPDB or patients with primary ovarian insufficiency with no family history. The results were published in the February 7 issues of the Journal of the Endocrine Society.
Welt wants to continue to mine UPDB to identify families that might be at risk for early ovarian failure. These families could help her identify additional genes that could increase risk for primary ovarian insufficiency.
“We can educate families with histories of ovarian failure on precautionary steps that they can take to ensure that they have fertility options in the future,” she said.
She also wants to determine whether any other diseases, like cardiovascular disease, autoimmune disease, and cancers, track with infertility associated with ovarian failure.
Welt credits the Utah Genome Project with recent advances in primary ovary insufficiency. “Every important gene identified to understand this condition during the last four years has been accomplished with the help of an affected family,” said Welt. “The large family histories available in the Utah Population Database is making the study of this condition faster and more efficient.”
The Utah Genome Project harnesses the power of UPDB, the world’s largest repository of family genetic histories that are linked to more than 22 million public health and clinical records, to discover new disease-causing genes and to develop genetic diagnostics and precision therapies that transform health care.
Contact: Rebekah Hendon
Email: Rebekah.Hendon@utah.edu