Novel inactivating mutations in the FSH receptor cause premature ovarian insufficiency with resistant ovary syndrome Wen-Bin He, Juan Du, Xiao-Wen Yang,

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Novel inactivating mutations in the FSH receptor cause premature ovarian insufficiency with resistant ovary syndrome Wen-Bin He, Juan Du, Xiao-Wen Yang, Wen Li, Wei-Lin Tang, Can Dai, Yong-Zhe Chen, Ya-Xin Zhang, Guang-Xiu Lu, Ge Lin, Fei Gong, Yue-Qiu Tan Reproductive BioMedicine Online Volume 38, Issue 3, Pages 397-406 (March 2019) DOI: 10.1016/j.rbmo.2018.11.011 Copyright © 2018 Reproductive Healthcare Ltd. Terms and Conditions

Figure 1 Pedigree and Sanger sequencing analysis of the FSH receptor gene (FSHR) in three Han Chinese families. Affected members are indicated with filled symbols; unaffected relatives are indicated by open symbols; heterozygous carriers are indicated with a dot in the middle of the symbol. The number of siblings is written inside the symbol. Arrows indicate the proband. Brackets are used for adoption, and adoptive parents are denoted by dashed lines of descent. Numbers are allotted to the family members whose DNA samples were used in this study. Panel A: Sanger sequencing confirmed that in family I, the proband's unaffected parents are heterozygous carriers of the FSHR mutation c.419delA, whereas their first-generation offspring are all homozygous. Panel B: in family II, both affected women are homozygous for the novel missense FSHR mutation c.1510C>T; however, their parents and brother are heterozygous. The mutation is absent in the unaffected sisters. Panel C: in family III, both affected women were compound heterozygous for c.44G>A and had a microdeletion of FSHR. The sister having mothered two sons (III-1) was heterozygous for c.44G>A, while her father had only the WT sequence at this position, but had a microdeletion of FSHR. Another sister, having mothered two daughters (III-3), lacked the variation and the microdeletion. WT = wild-type FSHR; MT = mutant FSHR; MT1 = c.44G>A of FSHR; MT2 = deletion of exons 1 and 2 of FSHR. Reproductive BioMedicine Online 2019 38, 397-406DOI: (10.1016/j.rbmo.2018.11.011) Copyright © 2018 Reproductive Healthcare Ltd. Terms and Conditions

Figure 2 Bioinformatic analysis and cAMP production assay of the three novel FSH receptor gene (FSHR) mutations. Panel A: homozygosity mapping of the proband of family II. Homozygous regions with marked signals are indicated. The asterisk indicates the area where FSHR is located. Panel B: proline at position 504 is highly conserved in different animal species, while glycine at position 15 is only conserved from Pan troglodytes to Mus musculus. Panel C: prediction of the signal peptide cleavage site in the WT FSHR and the p.Gly15Asp substitution performed by SignalP 4.1 server. The algorithm predicted a marked reduction of the cleavage site probability (from 0.478 to 0.195) for the p.Gly15Asp substitution. A arrow indicates the position of the WT and mutant signal peptide cleavage sites; C-score: raw cleavage site score; S-score: signal peptide score; Y-score: geometric average of the C-score and the slope of the S-score. Panel D: modelling of the FSHR mutations. The SWISS-MODEL software revealed that the frameshift mutation, c.419delA, in FSHR leads to the formation of a truncated protein. The angle between residue 504 and the fifth transmembrane helix was increased when Pro504 FSHR was compared with the predicted model of WT FSHR. A hydrogen bond between Gly15 and His19 was broken and three redundant hydrogen bonds were formed between Gly15 and two amino acid (Cys18 and Ser13) when Gly15 mutated to Asp in FSHR. Panel E: the result of quantitative real-time PCR. The father (II1) and two affected women (III2 and III4) from family III were carriers with deletion of exons 1 and 2 of FSHR. The two unaffected sisters (III1 and III3) lacked the microdeletion. Panel F: a dose-dependent increase in cAMP production on FSH stimulation was observed in cells expressing the WT FSHR, which was almost completely absent in the cells transfected with the mutated receptors. Data shown are mean ± SEM of three independent experiments performed in duplicate. Reproductive BioMedicine Online 2019 38, 397-406DOI: (10.1016/j.rbmo.2018.11.011) Copyright © 2018 Reproductive Healthcare Ltd. Terms and Conditions