Functional study of a novel missense single‐nucleotide variant of NUP 107 in two daughters of M exican origin with premature ovarian insufficiency

Abstract Background Hypergonadotropic hypogonadism ( HH ) is a genetically heterogeneous disorder that usually presents with amenorrhea, atrophic ovaries, and low estrogen. Most cases of HH are idiopathic and nonsyndromic. Nucleoporin 107 ( NUP 107 ), a protein involved in transport between cytoplasm and nucleus with putative roles in meiosis/mitosis progression, was recently implicated as a cause of HH . We identified a NUP 107 genetic variant in a nonconsanguineous family with two sisters affected with primary amenorrhea and HH, and generated a mouse model that carried the human variant. Methods We performed a high‐resolution X‐chromosome microarray and whole exome sequencing on parents and two sisters with HH to identify pathogenic variants. We generated a mouse model of candidate NUP 107 variant using CRISPR /Cas9. Results Whole exome sequencing identified a novel and rare missense variant in the NUP 107 gene (c.1063C>T, p.R355C) in both sisters with HH . In order to determine functional significance of this variant, we used CRISPR /Cas9 to introduce the human variant into the mouse genome. Mice with the homolog of the R355C variant, as well as the nine base pairs deletion in Nup107 had female subfertility. Conclusions Our findings indicate that NUP 107 R355C variant falls in the category of variant of unknown significance as the cause of HH and infertility.