A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency.
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.
['Fouquet|Baptiste|B|http://orcid.org/0000-0003-2069-1956', 'Pawlikowska|Patrycja|P|', 'Caburet|Sandrine|S|http://orcid.org/0000-0002-7404-8213', 'Guigon|Celine|C|', 'Mäkinen|Marika|M|', 'Tanner|Laura|L|', 'Hietala|Marja|M|', 'Urbanska|Kaja|K|', 'Bellutti|Laura|L|', 'Legois|Bérangère|B|', 'Bessieres|Bettina|B|', 'Gougeon|Alain|A|', 'Benachi|Alexandra|A|', 'Livera|Gabriel|G|http://orcid.org/0000-0001-8436-4730', 'Rosselli|Filippo|F|https://orcid.org/0000-0003-1080-5745', 'Veitia|Reiner A|RA|http://orcid.org/0000-0002-4100-2681', 'Misrahi|Micheline|M|http://orcid.org/0000-0002-5379-8859']
D000328:Adult D002869:Chromosome Aberrations D004265:DNA Helicases D052236:Fanconi Anemia Complementation Group D2 Protein D005260:Female D020022:Genetic Predisposition to Disease D005838:Genotype D059765:Homologous Recombination D006720:Homozygote D006801:Humans D008297:Male D008875:Middle Aged D009154:Mutation D010053:Ovary D010375:Pedigree D010641:Phenotype D016649:Primary Ovarian Insufficiency D054875:Ubiquitination D000073359:Whole Exome Sequencing D055815:Young Adult
FANCM mutation primary ovarian insufficiency exome sequencing Mitomycin C human human biology medicine replication inhibitor