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

Baptiste Fouquet,Marja Hietala,Reiner A Veitia,Laura Tanner,Celine Guigon,Kaja Urbanska,Filippo Rosselli,Bettina Bessieres,Marika Mäkinen,Bérangère Legois,Alexandra Benachi,Gabriel Livera,Micheline Misrahi,Sandrine Caburet,Laura Bellutti,Alain Gougeon,Patrycja Pawlikowska

doi:10.7554/elife.30490

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.

Highlights

Primary Ovarian Insufficiency (POI) affects about 1% of women under forty years
The two patients with POI studied here belong to a consanguineous family and are homozygous for the FANCM mutation inherited from their parents
Our FANCM mRNA and protein expression studies in the developing human ovary suggest that the expression of FANCM starts in mitotic germ cells notably along chromosome axes and increases at the onset of meiosis that are maintained up to the diplotene stage in follicles

Summary

Introduction

Primary Ovarian Insufficiency (POI) affects about 1% of women under forty years. It is often diagnosed too late, generating infertility and significant morbidity and mortality due to steroid-deprivation associated symptoms. Infertility is usually definitive but resumption of ovarian function occurs in ~24% of cases (Tucker et al, 2016). ODG2 # 300510 ODG3 # 614324, ODG4 # 616185) and remains idiopathic in ~70% of the Fouquet et al eLife 2017;6:e30490.

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