Novel variants in PABPC1L cause female infertility due to oocyte maturation defects.

PURPOSE: Oocyte maturation defects are one of the common clinical phenotypes contributing to recurrent IVF/ICSI failures and female infertility. We aimed to identify novel pathogenic variants responsible for oocyte maturation defects. METHODS: Whole-exome sequencing and in silico analysis were used to identify variants in disease-causing genes in a cohort of 442 female infertility patients with oocyte maturation defects. In vitro functional studies were performed to validate the destructive effects and pathogenicity of the novel variants. RESULTS: We identified five novel PABPC1L variants (c.280C > A (p.Arg94Ser), c.283A > T (p.Lys95*), c.611A > G (p.Glu204Gly), c.583G > T (p.Val195Leu), and c.691C > T (p.Arg231Trp)) in two independent infertile families. These variants followed an autosomal recessive inheritance pattern. Western blotting analysis confirmed that all the novel variants led to the downregulation of PABPC1L protein expression in HEK293T cells. Immunofluorescence results showed that the nonsense variant c.283A > T (p.Lys95*) altered the cytoplasmic localization of PABPC1L in HeLa cells. In addition, three-dimensional molecular modeling and cycloheximide chase assay indicated that all four missense variants impair the stability of the PABPC1L protein. CONCLUSION: Our findings expand the mutational spectrum of the pathogenic gene PABPC1L, further highlight its essential function in female reproduction, and provide new support for the genetic diagnosis of female infertility.