%0 Journal Article %T A homozygous $FANCM$ mutation underlies a familial case of non-syndromic primary ovarian insufficiency %+ Hôpital Bicêtre %+ Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine) %+ Stabilité Génétique et Oncogenèse (UMR 8200) %+ Institut Jacques Monod (IJM (UMR_7592)) %+ Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)) %+ Turku University Hospital (TYKS) %+ Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)) %+ Institut de Radiobiologie Cellulaire et Moléculaire (IRCM) %+ Département d’Histologie-Embryologie-Cytogénétique %+ Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL) %+ Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP) %+ Université Paris-Saclay %+ Institut Jacques Monod (IJM (UMR_7592)) %A Fouquet, Baptiste %A Pawlikowska, Patrycja %A Caburet, Sandrine %A Guigon, Céline %A Mäkinen, Marika %A Tanner, Laura %A Hietala, Marja %A Urbanska, Kaja %A Bellutti, Laura %A Legois, Bérangère %A Bessières, Bettina %A Gougeon, Alain %A Benachi, Alexandra %A Livera, Gabriel %A Rosselli, Filippo, L %A Veitia, Reiner %A Misrahi, Micheline %Z Fondation pour la Recherche Médicale (Grant DEQ20150331757) %Z Ligue Contre le Cancer %< avec comité de lecture %@ 2050-084X %J eLife %I eLife Sciences Publication %V 6 %P e30490 %8 2017-12-12 %D 2017 %R 10.7554/eLife.30490 %Z Life Sciences [q-bio]Journal articles %X Primary Ovarian Insufficiency (POI) affects ~1% of women under forty. Exome sequencing of two Finnish sisters with non-syndromic POI revealed a homozygous mutation in FANCM, leading to a truncated protein (p.Gln1701*). FANCM is a DNA-damage response gene whose heterozygous mutations predispose to breast cancer. Compared to the mother’s cells, the patients’ lymphocytes displayed higher levels of basal and mitomycin C (MMC)-induced chromosomal abnormalities. Their lymphoblasts were hypersensitive to MMC and MMC-induced monoubiquitination of FANCD2 was impaired. Genetic complementation of patient’s cells with wild-type FANCM improved their resistance to MMC re-establishing FANCD2 monoubiquitination. FANCM was more strongly expressed in human fetal germ cells than in somatic cells. FANCM protein was preferentially expressed along the chromosomes in pachytene cells, which undergo meiotic recombination. This mutation may provoke meiotic defects leading to a depleted follicular stock, as in Fancm$^{-/-}$ mice. Our findings document the first Mendelian phenotype due to a biallelic FANCM mutation. %G English %2 https://hal.science/hal-02391886/document %2 https://hal.science/hal-02391886/file/bfa_elife.pdf %L hal-02391886 %U https://hal.science/hal-02391886 %~ INSERM %~ CEA %~ UNIV-PARIS7 %~ CNRS %~ UNIV-LYON1 %~ UNIV-PSUD %~ IJM %~ APHP %~ FNCLCC %~ IGR %~ CEA-UPSAY %~ USPC %~ UNIV-PARIS-SACLAY %~ UNIV-PSUD-SACLAY %~ CEA-UPSAY-SACLAY %~ IGR-SACLAY %~ JACOB %~ CEA-DRF %~ CRCL %~ CHU-UNIV-PARIS5 %~ UDL %~ UNIV-LYON %~ UNIV-PARIS %~ UP-SCIENCES %~ BFA %~ GS-HEALTH-DRUG-SCIENCES %~ UMR-SGCSR %~ FRM