Institut Jacques Monod, Université Paris Diderot, Paris, France
Celine Guigon
Université Paris-Diderot, CNRS, UMR 8251, INSERM, U1133, Paris, France
Marika Mäkinen
Department of Clinical Genetics, Turku University Hospital, Turku, Finland
Laura Tanner
Department of Clinical Genetics, Turku University Hospital, Turku, Finland
Marja Hietala
Department of Clinical Genetics, Turku University Hospital, Turku, Finland
Kaja Urbanska
CNRS UMR8200, Université Paris Sud, Université Paris Saclay, Villejuif, France
Laura Bellutti
UMR967 INSERM, CEA/DRF/iRCM/SCSR/LDG, Université Paris Diderot, Sorbonne Paris Cité, Université Paris-Sud, Université Paris-Saclay, Fontenay aux Roses, France
Bérangère Legois
Institut Jacques Monod, Université Paris Diderot, Paris, France
Bettina Bessieres
Department of Histology, Embryology and Cytogenetics, Hôpital Necker-enfants malades, Paris, France
Alain Gougeon
UMR Inserm 1052, CNRS 5286, Faculté de Médecine Laennec, Lyon, France
Alexandra Benachi
Department of Obstetrics and Gynaecology, AP-HP, Université Paris-Sud, Université Paris-Saclay, Clamart, France
UMR967 INSERM, CEA/DRF/iRCM/SCSR/LDG, Université Paris Diderot, Sorbonne Paris Cité, Université Paris-Sud, Université Paris-Saclay, Fontenay aux Roses, France
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.