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

Authors :
Baptiste Fouquet
Patrycja Pawlikowska
Sandrine Caburet
Celine Guigon
Marika Mäkinen
Laura Tanner
Marja Hietala
Kaja Urbanska
Laura Bellutti
Bérangère Legois
Bettina Bessieres
Alain Gougeon
Alexandra Benachi
Gabriel Livera
Filippo Rosselli
Reiner A Veitia
Micheline Misrahi
Source :
eLife, Vol 6 (2017)
Publication Year :
2017
Publisher :
eLife Sciences Publications Ltd, 2017.

Abstract

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.

Details

Language :
English
ISSN :
2050084X
Volume :
6
Database :
Directory of Open Access Journals
Journal :
eLife
Publication Type :
Academic Journal
Accession number :
edsdoj.56f7045340a14393b3106a4985fe8175
Document Type :
article
Full Text :
https://doi.org/10.7554/eLife.30490