Infertile females with biallelic mutations in APC/C genes are characterized by oocyte or early embryo defects.

PURPOSE: The objective of this study was to elucidate the role of anaphase promoting complex/cyclosome (APC/C)-related genes in cases of female infertility characterized by disturbances in oocyte maturation, failure of fertilization, and cessation of early embryonic growth among three distinct Chinese familial lineages. METHODS: We conducted whole-exome sequencing of patients with female infertility from 639 unrelated Chinese families and three probands with APC/C gene mutations were screened. Structure modeling and in vitro experiments were performed to analyze the effects of CDC23 and APC13 variants. RESULTS: We identified six rare missense variants in APC/C genes, including two compound heterozygous missense variants of CDC23 (c.A1277G, c.A833G, c.C182T and c.C301T) from case 1 and case 2 and one compound heterozygous variant of APC13 (c.C6A and c.116_126del) from case 3. These APC/C gene mutations all showed a recessive inheritance pattern. These mutations are conserved across different species. Mutation Taster, SIFT and PPH2 forecast that these variants are inclined towards exerting a deleterious effect. Structural analysis indicated that these mutations may result in changes in the chemical bonds between themselves and other APC/C subunits. In vitro experimental data suggested that mutations associated with CDC23 result in dysregulated protein expression, whereas missense mutation in APC13 is implicated in aberrant cellular localization patterns. CONCLUSION: Our findings expand the genetic spectrum of APC/C genes, especially CDC23 and APC13 in female infertility, indicating that the significance of APC/C genes in female sterility should be emphasized in the future. And it provides a new diagnostic and therapeutic target for genetic counseling.