New MCM8 mutation associated with premature ovarian insufficiency and chromosomal instability in a highly consanguineous Tunisian family Nouha Bouali,

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New MCM8 mutation associated with premature ovarian insufficiency and chromosomal instability in a highly consanguineous Tunisian family Nouha Bouali, Ph.D., Bruno Francou, Pharm.D., Ph.D., Jérôme Bouligand, Pharm.D., Ph.D., Dilek Imanci, B.S., Sarra Dimassi, M.D., Lucie Tosca, Ph.D., Monia Zaouali, M.D., Soumaya Mougou, M.D., Ph.D., Jacques Young, M.D., Ph.D., Ali Saad, M.D., Ph.D., Anne Guiochon-Mantel, M.D., Ph.D. Fertility and Sterility Volume 108, Issue 4, Pages 694-702 (October 2017) DOI: 10.1016/j.fertnstert.2017.07.015 Copyright © 2017 American Society for Reproductive Medicine Terms and Conditions

Fertility and Sterility 2017 108, 694-702DOI: (10. 1016/j. fertnstert Copyright © 2017 American Society for Reproductive Medicine Terms and Conditions

Figure 1 Family pedigree and MCM8 mutation sequencing. (A) Pedigree of a highly consanguineous Tunisian family. Family members are designated by Arabic numerals. The asterisks mark individuals analyzed by next-generation sequencing technology and the MCM8 genotype is indicated below each individual. MT = mutated allele; WT = wild-type allele. Arrows indicate the proband (V-5) and the unaffected sister (V-6) tested for chromosomal instability. (B) Sanger sequencing was used to validate genotypes and representative chromatograms are shown. Individuals who are heterozygous for the c.482A>C; p.His161Pro MCM8 variant show overlapping A and C peaks (upper graph). Affected individuals homozygous for the c.482A>C; p.His161Pro MCM8 variant have a single C peak (middle graph) unlike an unaffected control who has a single A peak (lower graph). (C) Evolutionary conservation of His161 (red arrow) across species. Fertility and Sterility 2017 108, 694-702DOI: (10.1016/j.fertnstert.2017.07.015) Copyright © 2017 American Society for Reproductive Medicine Terms and Conditions

Figure 2 The c.482A>C; p.His161Pro MCM8 mutation impairs DNA break repair. Cells derived from peripheral lymphocytes of homozygous affected individual induced by mitomycin C (MMC) show an impaired ability to repair DNA breaks. Three samples were tested. For each sample, cells were cultured in the presence of increasing MMC concentrations (50, 150, and 300 nM). Figures of representative metaphase spreads exposed to 300 nM MMC from (A) a healthy fertile control woman with WT/WT genotype, (B) a heterozygous unaffected individual with WT/MT genotype (V-6). and (C) a homozygous affected female MT/MT genotype (V-5). Red arrows indicate the observed chromosomal breaks. MT = mutated allele; WT = wild-type allele. (D) Bar graphs show the number of breaks per cell in homozygous (blue bar) and heterozygous (red bars) individuals, compared with a WT control (green bars) for each MMC concentration (0, 50, 150, and 300 nM). A total of 50 metaphase spreads per sample were evaluated to check chromosome aberrations and breaks. Nonparametric Kruskall-Wallis test and post-test Dunn's multiple comparison were used to compare median values of chromosomal breaks at each concentration between affected homozygous, unaffected heterozygous sisters and WT control. SD is shown as error bars.*P values <.05 were considered statistically significant. **P value <.001. Fertility and Sterility 2017 108, 694-702DOI: (10.1016/j.fertnstert.2017.07.015) Copyright © 2017 American Society for Reproductive Medicine Terms and Conditions