Nonsense mutation of EMX2 is potential causative for uterus didelphysis First molecular explanation for isolated incomplete müllerian fusion

We identified a novel nonsense mutation p.E142X in EMX2, resulting in truncated protein with a dominant negative effect. It reinforced the likelihood that EMX2 contributed to the pathophysiology of IMF.

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Shan Liu, M.D., Ph.D., Xuan Gao, M.D., Yingying Qin, M.D., Ph.D., Wen Liu, M.S., Tao Huang, M.S., Jinlong Ma, M.D., Ph.D., Joe Leigh Simpson, M.D., Ph.D., Zi-Jiang Chen, M.D., Ph.D.

Volume 103, Issue 3, Pages 769-774



To investigate the association between human empty spiracles homeobox 2 gene (EMX2) and incomplete müllerian fusion (IMF).


Case-control study.


University-based hospital.


Cohort of 517 clinically well-characterized IMF cases and 563 control women.



Main Outcome Measure(s):

In cases and control women, direct sequencing of EMX2 exons and further functional studies; for functional studies, wild-type and mutant EMX2 expression plasmids constructed; human embryonic kidney cells (HEK293FT) transfected with empty vector, wild-type EMX2, mutant EMX2, and 1:1 combination (wild-type/mutant plasmids) with additional functional studies performed to clarify the deleterious effect of the novel mutation detected.


A novel nonsense mutation p.E142X was detected in one woman with a didelphic uterus (1 of 517, 0.19%). The results of Western blot analysis confirmed that the mutation caused a truncated protein as predicted, and functional studies proved that it resulted in a dominant negative effect.


The novel nonsense mutation we detected-EMX2, p.E142X- resulted in a dominant negative effect. The functional data were exemplified in HEK293FT cells. This reinforced the likelihood that EMX2 contributed to the pathophysiology of IMF. Although it is uncommon (0.19%), EMX2 is the first gene identified that if perturbed may cause isolated IMF.

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Fertility and Sterility

Editorial Office, American Society for Reproductive Medicine

Fertility and Sterility® is an international journal for obstetricians, gynecologists, reproductive endocrinologists, urologists, basic scientists and others who treat and investigate problems of infertility and human reproductive disorders.