Corrine Welt, MD, professor of internal medicine at University of Utah Health was faced with a mystery. She learned of a Yemini family where every woman, aged 16-27, suffered from primary ovarian insufficiency (POI).
While most women begin menopause around age 50, one percent of women worldwide have POI, characterized by menopause that begins before the age of 40. Women suffering an extreme form of this disorder, such as women in the Yemini family, fail to go through puberty.
“This is the only fertility problem we cannot fix,” said Welt. “The most devastating thing about this diagnosis is that it is unexpected, and women are left grieving for a family they cannot have.”
Welt coordinated with her colleagues in Saudi Arabia to use a new database being assembled in the Kingdom to help identify genetic underpinnings of POI in this family. The database is similar to the Utah Population Database that matches public and health records to extended families.
“We know only a few of the genes that are in some way associated with POI,” said Welt.
Welt applied a new tool, called Truploidy, developed by the USTAR Center for Genetic Discovery to scan the genome of every member of the Yemini family. With this technology, she could identify the sections of the genome that are shared between the siblings. They compared the family’s results to a control population consisting of healthy individuals from the new database to look for changes. They narrowed their search from 23 to 4 genes.
The women in the study shared a homozygous mutation in the PSMC3IP gene. New to this study, their brother also carried the same homozygous PSMC3IP mutation. This mutation prevented the women in the family from going through puberty. The male in the family did complete puberty, but he was unable to produce viable sperm.
The researchers looked for the same mutation in European women but have not yet found one. They will continue their studies to identify important pathways to help look for candidate genes to help all women and men affected by POI.
“If we can find genes that can be targeted, we can develop a DNA test,” Welt said. “With a test in hand, we can identify women early and educate them about their options so they can prepare for a family they may want to have.”
The article, titled “Primary Ovarian Insufficiency and Azoospermia in Carriers of a Homozygous PSMC3IP Stop Gain Mutation” was published by The Journal of Clinical Endocrinology & Metabolism on February 1, 2018. This work was funded by the National Cancer Institute and the National Institute of General Medical Sciences.