A homozygous $FANCM$ mutation underlies a familial case of non-syndromic primary ovarian insufficiency

Baptiste Fouquet (1, 2) , Patrycja Pawlikowska (3) , Sandrine Caburet (4) , Céline Guigon (5) , Marika Mäkinen (6) , Laura Tanner (6) , Marja Hietala (6) , Kaja Urbanska (3) , Laura Bellutti (7, 8) , Bérangère Legois (4) , Bettina Bessières (9) , Alain Gougeon (10) , Alexandra Benachi (11, 12) , Gabriel Livera (7) , Filippo L Rosselli (3) , Reiner Veitia (13) , Micheline Misrahi (1)

1 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
2 UP11 UFR Médecine - Université Paris-Sud - Paris 11 - Faculté de médecine
3 UMR 8200 - Stabilité Génétique et Oncogenèse
4 IJM (UMR_7592) - Institut Jacques Monod
5 BFA (UMR_8251 / U1133) - Unité de Biologie Fonctionnelle et Adaptative
6 TYKS - Turku University Hospital
7 SCSR (U_967) - Stabilité génétique, Cellules Souches et Radiations
8 IRCM - Institut de Radiobiologie Cellulaire et Moléculaire
9 Département d’Histologie-Embryologie-Cytogénétique
10 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
11 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
12 Université Paris-Saclay
13 IJM (UMR_7592) - Institut Jacques Monod

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.

Domaines: Sciences du Vivant [q-bio]

Baptiste Fouquet, Patrycja Pawlikowska, Sandrine Caburet, Céline Guigon, Marika Mäkinen, et al.. A homozygous $FANCM$ mutation underlies a familial case of non-syndromic primary ovarian insufficiency. eLife, 2017, 6, pp.e30490. ⟨10.7554/eLife.30490⟩. ⟨hal-02391886⟩