A heterozygous hypomorphic mutation of Fanca causes impaired follicle development and subfertility in female mice
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ORIGINAL ARTICLE
A heterozygous hypomorphic mutation of Fanca causes impaired follicle development and subfertility in female mice Yuncheng Pan1 · Xi Yang1 · Feng Zhang1,2 · Siyuan Chen1 · Zixue Zhou1 · Hao Yin3 · Hui Ma3 · Lingyue Shang1 · Jialin Yang1 · Guoqing Li1 · Yingchen Wang1 · Li Jin1 · Qinghua Shi3 · Yanhua Wu1,2,4 Received: 14 February 2020 / Accepted: 22 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract 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. Keywords FANCA · Mice · Fertility · Follicular development · DNA repair
Introduction Communicated by Stefan Hohmann. Yuncheng Pan, Xi Yang and Feng Zhang contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00438-020-01730-5) contains supplementary material, which is available to authorized users. * Qinghua Shi [email protected]
Reproduction is an important process in human life. Nowadays, infertility is becoming a common human health threat affecting approximately more than 186 million people around the globe (Inhorn and Patrizio 2015). In women, fertility declines from 25–30 years-old (Eijkemans et al. 2014). The etiologies of female infertility/subfertility 3
First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, CAS Center for Excellence in Molecular Cell Science, University of Science and Technology of China, Hefei 230027, Anhui, China
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National Dem
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