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

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.

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.

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.

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.