Association of FOXL2 and ERCC6 variants with premature ovarian insufficiency and their potential use in clinical IVF guidance

• Published in: Gene Vol. 933; p. 148946
• Main Authors: Gu, Meng, Fang, Jiajun, Shao, Zhongmei, Yu, Hui, Guo, Senchao, Gao, Yang, He, Xiaojin, Xu, Yuping, Lv, Mingrong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.01.2025
• Subjects: Adult; Assisted reproductive technology; blood; DNA Helicases - genetics; DNA Repair Enzymes; DNA-Binding Proteins - genetics; ERCC6; Exome Sequencing - methods; Female; Female infertility; Fertilization in Vitro - methods; Forkhead Box Protein L2 - genetics; FOXL2; genes; Genetic Predisposition to Disease; heterozygosity; Heterozygote; Humans; Infertility, Female - genetics; Mutation, Missense; patients; Poly-ADP-Ribose Binding Proteins; Premature ovarian insufficiency; Primary Ovarian Insufficiency - genetics; protein synthesis; therapeutics; SIFT; WES; MCM8; Assisted reproductive technology; WB; RIPA; BMP15; PolyPhen-2; SNP; Female infertility; MI; BPES; qRT-PCR; TBST; FOXL2; POI; Premature ovarian insufficiency; MII; IVF-ET; GV; CS; GDF9; SDS-PAGE; MSH4; FSHR; NOBOX; ERCC6; GAPDH; PN
• ISSN: 0378-1119; 1879-0038; 1879-0038
• DOI: 10.1016/j.gene.2024.148946

•We identified three pathogenic variants of FOXL2 and ERCC6 genes in our cohort, which enriched the genetic variants spectrum of POI.•Variants of the FOXL2 and ERCC6 genes decreased their mRNAs and proteins levels.•We firstly provide the IVF clinical outcomes of FOXL2 and ERCC6 mutated subjects. Premature ovarian insufficiency (POI) is the main cause of infertility in women. Some cases of POI are thought to be caused by genetic defects and the clinical outcomes of these patients are unknown. Here, we performed whole-exome sequencing of the peripheral blood of a cohort of 55 subjects with POI and identified one heterozygous missense variant in FOXL2 (c.1045G>C; p.Arg349Gly) and two heterozygous missense variants in ERCC6 (c.379G>A; p.Val127Ile and c.4223A>C; p.Glu1408 Ala) in four POI patients. All of these heterozygous mutations were predicted to be deleterious and were parentally inherited from their heterozygous fathers. The mRNA and protein expression of FOXL2 and ERCC6 were absent or decreased in the patients. The patients carrying the variants of FOXL2 (c.1045G>C; p.Arg349Gly) and ERCC6 (c.379G>A; p.Val127Ile) failed to conceive in two and four assisted reproductive cycles, respectively. Another patient and her sister carrying the ERCC6 (c.4223A>C; p.Glu1408 Ala) variant achieved good clinical outcomes after assisted reproductive therapy. Our findings support the possible roles of FOXL2 and ERCC6 in POI and might contribute to the genetic counseling of POI patients.