LAUSR

Inherited dominant mutations in PANX1 cause female infertility characterized by oocyte death. A vital gene for oocytes Infertility is common in both males and females, but the biological causes of female infertility are not as well understood. Sang et al. identified four families with inherited female infertility and a similar phenotype that presents with oocyte death in vitro, either before or shortly after fertilization. The authors found that this phenotype was caused by mutations in pannexin 1, a channel protein involved in cellular communication. The authors examined the mechanism of pathogenesis associated with these mutations and showed that a patient-derived mutation causes the same pattern of oocyte death in a mouse model, providing a possible target for therapeutic development. Connexins and pannexins are two protein families that play an important role in cellular communication. Pannexin 1 (PANX1), one of the members of pannexin family, is a channel protein. It is glycosylated and forms three species, GLY0, GLY1, and GLY2. Here, we describe four independent families in which mutations in PANX1 cause familial or sporadic female infertility via a phenotype that we term “oocyte death.” The mutations, which are associated with oocyte death, alter the PANX1 glycosylation pattern, influence the subcellular localization of PANX1 in cultured cells, and result in aberrant PANX1 channel activity, ATP release in oocytes, and mutant PANX1 GLY1. Overexpression of a patient-derived mutation in mice causes infertility, recapitulating the human oocyte death phenotype. Our findings demonstrate the critical role of PANX1 in human oocyte development, provide a genetic explanation for a subtype of infertility, and suggest a potential target for therapeutic intervention for this disease.