A heterozygous hypomorphic mutation of Fanca causes impaired follicle development and subfertility in female mice

• Published in: Molecular genetics and genomics : MGG 2021, Vol.296 (1), p.103-112
• Main Authors: Pan, Yuncheng, Yang, Xi, Zhang, Feng, Chen, Siyuan, Zhou, Zixue, Yin, Hao, Ma, Hui, Shang, Lingyue, Yang, Jialin, Li, Guoqing, Wang, Yingchen, Jin, Li, Shi, Qinghua, Wu, Yanhua
• Format: Article
• Language: English
• Subjects: Aging; Alkylating Agents - pharmacology; Anemia; Animal Genetics and Genomics; Animals; Base Sequence; Biochemistry; Biomedical and Life Sciences; Complementation; Deletion mutant; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA repair; DNA Repair - drug effects; Embryo fibroblasts; Embryo, Mammalian; FANCA protein; Fanconi Anemia Complementation Group A Protein - deficiency; Fanconi Anemia Complementation Group A Protein - genetics; Fanconi syndrome; Female; Females; Fertility; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Follicles; Gene deletion; Gene Expression; Genetic counseling; Genotypes; Hereditary diseases; Heterozygote; Human Genetics; Humans; Infertility - genetics; Infertility - metabolism; Infertility - pathology; Infertility, Female - genetics; Infertility, Female - metabolism; Infertility, Female - pathology; Life Sciences; Litter Size; Mice; Mice, Knockout; Microbial Genetics and Genomics; Mitomycin - pharmacology; Mitomycin C; Mutants; Original Article; Ovarian Follicle - metabolism; Ovarian Follicle - pathology; Ovaries; Phenotypes; Plant Genetics and Genomics; Primary Cell Culture; Primary Ovarian Insufficiency - genetics; Primary Ovarian Insufficiency - metabolism; Primary Ovarian Insufficiency - pathology; Sequence Deletion
• ISSN: 1617-4615; 1617-4623
• DOI: 10.1007/s00438-020-01730-5

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 in FANCA ( Fanconi anemia complementation group A ) induced premature ovarian insufficiency (POI). However, the genotype–phenotype correlation in POI caused by FANCA variants remains considerably uncertain. Herein, a heterozygous non-frameshift Fanca -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 female Fanca + /hypo mice compared to wild-type mice. Follicle counting revealed a consistent decreasing pattern of follicle numbers in Fanca + /hypo females compared to that in wild-type mice with aging. Furthermore, embryonic fibroblasts of Fanca + /hypo mice were hyper-responsive to Mitomycin C in vitro, demonstrating a partial loss of function of this hypomorphic Fanca mutant in DNA repair. Collectively, our experimental observations suggest that the hypomorphic Fanca allele is sufficient to reduce female fertility in mice, providing new insights into the genetic counseling of FANCA variants in subfertile women.