We have discovered a form of inherited and spontaneous pelvic organ prolapse (S-POP) in mice. The mutation appeared in a colony of transgenic mice. The phenotype has been isolated from the transgene in FVB/N mice by selective breeding. It is inherited as an autosomal dominant trait, is seen in both males and females and no precipitating event (such as pregnancy or parturition) is necessary. Pelvic organ prolapse (POP) is a common condition in women, estimated to affect up to one third of all women and up to half of all women over age fifty. The condition, which seems to manifest as defects in the supporting connective tissue of the pelvic organs, adversely affects quality of life and is a major health issue for women. The lifetime risk of undergoing surgery for pelvic floor disorders exceeds 11% by age eighty, and prolapse is the most common indication for hysterectomy in women over age fifty. Despite being a common problem, the etiology for pelvic organ prolapse is poorly understood. Current literature has correlated the development of pelvic organ prolapse with age, vaginal parity, increased infant birth weight, menopausal status, and genetic susceptibility. However, a detailed mechanism explaining the development of the connective tissue defects remains elusive. A specific genetic defect has not been identified, and identification of such a defect would have profound implications. Evidence for genetic susceptibility includes the fact that severe pelvic organ prolapse has been observed (with a familial association) in nulliparous women without other risk factors, as well as the fact that the majority of multiparous women do not develop symptoms of pelvic organ prolapse. In addition, ethnic and racial associations with pelvic organ prolapse have been described, indicating that women of European and Hispanic heritage are at higher risk for development of POP than African, Asian, or Native American women. The primary goal of this proposal is to identify the genetic mutation that causes S-POP in mice. The information may prove useful in identifying genetic factors associated with POP in humans. Furthermore, the mutation may cause other more subtle phenotypes that could be useful in modeling other human or animal diseases. The mutation will be mapped by crossing an S-POP male on FVB/NJ background to C57BL/6J females, back-crossing the progeny to C57BL/6J and SNP genotyping mice that develop S-POP. Candidate genes will be analyzed based on chromosomal locations, known functions and expression levels. The S-POP phenotype will be characterized using a combination of magnetic resonance microscopy, necrospy, and histology.
The goals of this project are to identify the mutation that causes inherited, spontaneous pelvic organ prolapse in mice and to describe in detail the anatomy of prolapse in mice. Pelvic organ prolapse is a common and serious problem in humans in which genetics play a major role. It is hoped that identification of the gene that causes prolapse in mice will lead to a better understanding of the developmental, environmental, and genetic origins of prolapse in humans.