A heterozygous hypomorphic mutation ofFancacauses impaired follicle development and subfertility in female mice

Reduced fertility is a common clinical feature of the individuals with Fanconi anemia (FA), a rare autosomal recessive disorder due to deficiency in FA pathway during DNA repair. Our previous study reported that the heterozygous pathogenic variants inFANCA(Fanconi anemia complementation group A) induced premature ovarian insufficiency (POI). However, the genotype-phenotype correlation in POI caused byFANCAvariants remains considerably uncertain. Herein, a heterozygous non-frameshiftFanca-mutated mouse strain (Fanca(+/hypo)) carrying a 9-bp deletion (c.3581del9, p.QEA1194-1196del) was generated. The mutant mice exhibited slightly decreased Fanca protein level in ovaries, suggesting the non-frameshift deletion mutant is hypomorphic. Female fertility test showed decreased number of litters, litter sizes and prolonged litter interval time in the femaleFanca(+/hypo)mice compared to wild-type mice. Follicle counting revealed a consistent decreasing pattern of follicle numbers inFanca(+/hypo)females compared to that in wild-type mice with aging. Furthermore, embryonic fibroblasts ofFanca(+/hypo)mice were hyper-responsive to Mitomycin C in vitro, demonstrating a partial loss of function of this hypomorphicFancamutant in DNA repair. Collectively, our experimental observations suggest that the hypomorphicFancaallele is sufficient to reduce female fertility in mice, providing new insights into the genetic counseling ofFANCAvariants in subfertile women.

Automated summary

The study established a mouse model with a heterozygous deletion mutation in the FANCA gene, showing that this hypomorphic gene mutation can reduce fertility in mice and lead to a gradual decrease in the number of follicles with aging.