NPSR1 gene discovered as a key cause of endometriosis

NPSR1 has been identified as a genetic cause of endometriosis, revealing a potential drug target that may lead to better therapies.

Woman holding stomach in pain next to scan of uterus

Researchers at the Baylor College of Medicine and the University of Wisconsin-Madison, both US, in collaboration with the University of Oxford, UK, and Bayer AG have discovered that the RPSR1 gene increases the risk of endometriosis. According to the team, their study reveals a potential drug target that may lead to improved therapy.

Scientists at the University of Oxford had previously found a genetic linkage to endometriosis on chromosome 7p13-15 by analysing DNA from families containing at least three women diagnosed with endometriosis. The Baylor team subsequently verified this genetic linkage in the DNA of rhesus monkeys with spontaneous endometriosis.

This validation led to further research through in-depth sequencing analysis of the endometriosis families that narrowed down the genetic cause to rare variants in the NPSR1 gene. Most of the women carrying these rare variants had stage III/IV disease. The researchers then sequenced rhesus monkeys and again showed suggestive evidence also in this species. Finally, a study of more than 11,000 women, including patients with endometriosis and healthy women, identified a specific common variant in the NPSR1 gene also associated with stage III/IV endometriosis.

“This is one of the first examples of DNA sequencing in non-human primates to validate results in human studies and the first to make a significant impact on understanding the genetics of common, complex metabolic diseases,” commented senior author Dr Jeffrey Rogers. “The primate research really helped to provide confidence at each step of the genetic analysis in humans and gave us motivation to carry on chasing these particular genes.”

The team stated that the insights revealed in this genetic analysis point to a potential new drug target. They used an NPSR1 inhibitor to block protein signalling of that gene in cellular assays and then in mouse models of endometriosis. They found that this treatment led to reduced inflammation and abdominal pain, thereby identifying a target for future research in treating endometriosis.

“This is an exciting new development in our quest for new treatments of endometriosis, a debilitating and underrecognised disease affecting 190 million women worldwide. We need to do further research on the mechanism of action and the role of the genetic variants in modulation of the gene’s effects in specific tissues,” explained Dr Krina Zondervan, corresponding author of the study. “However, we have a promising new non-hormonal target for further investigation and development that appears to address directly the inflammatory and pain components of the disease.”

The study was published in Science Translational Medicine.

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