About one in 100 women under the age of 40 experience a condition known as primary ovarian insufficiency, which is sometimes known as premature menopause. Women with this condition may have fewer egg cells and are usually infertile. Women with primary ovarian insufficiency are also more at risk of other diseases, including the bone disorder osteoporosis and cardiovascular diseases. The condition is thought to have a genetic basis in part, although so far its causes are largely unknown.

Fouquet, Pawlikowska et al. looked at all the genes in genomes of three women in one Finnish family: two sisters and their mother. Both of the sisters had primary ovarian insufficiency, but were otherwise healthy. Their mother did not have the condition. The genetic analysis identified a mutation in a gene called FANCM, which is involved in the cell’s repair response to DNA damage and has recently been linked to breast cancer. This gene is mostly active in egg cells within the ovary. The sisters’ protein made from this mutated copy of the gene was cut short compared with the protein produced by the mother’s FANCM gene.

Due to the mutation, the sisters were more sensitive to chemicals that can damage the DNA, effectively making their genome less stable. The affected sisters also had higher levels of abnormalities in the chromosomes compared with their unaffected mother. Fouquet, Pawlikowska et al. then inserted a healthy version of the FANCM gene into the sisters’ cells. This reversed the sensitivity of the sisters’ cells to DNA-damaging chemicals.

The findings confirm a genetic link between primary ovarian insufficiency and genes responsible for DNA repair. Mutations in these genes can also make people more at risk of certain cancers. The findings point towards offering some women who have primary ovarian insufficiency in-depth genetic counselling with a long-term follow-up, when alterations of cancer-susceptibility genes are responsible for their condition.

Primary Ovarian Insufficiency (POI) affects about 1% of women under forty years. It is often diagnosed too late, thus 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). POI is etiologically heterogeneous (OMIM: ODG1 # 233300. ODG2 # 300510 ODG3 # 614324, ODG4 # 616185) and remains idiopathic in ~70% of the cases, but a number of genetic variants have been identified, including mutations in meiotic and DNA repair genes (Tucker et al., 2016). Consistently, several DNA repair and genomic instability disorders, such as Fanconi anemia (FA), are known to be associated with hypogonadism, ovarian failure and/or infertility. FA is a bone marrow failure syndrome accompanied by developmental defects, predisposition to leukemia, chromosome fragility and hypersensitivity to DNA interstrand crosslinks (ICL) (Bogliolo and Surrallés, 2015; Ceccaldi et al., 2016). The products of the 21 genes (FANCA to FANCV) whose loss-of-function has been associated to FA are subdivided into three functional groups (Bogliolo and Surrallés, 2015; Ceccaldi et al., 2016; Wang, 2007). The first one, the FANCcore complex consisting of seven FA proteins (A, B, C, E, F, G, and L) and two FA-associated proteins (FAAP20 and FAAP100), is assembled in response to DNA damage and/or stalled replication forks to monoubiquitinate FANCD2 and FANCI (the second group). This monoubiquitination allows the FANCD2-FANCI heterodimer to coordinate the DNA repair/replication rescue activities of the third group of FANC proteins, which includes nucleases and proteins involved in homologous recombination. The third group includes BRCA1, BRCA2, RAD51, PALPB2 and BRIP1, whose mutations predispose to breast and ovarian cancer (BOC) (Bogliolo and Surrallés, 2015). However, a more recent analysis reconsidered the role of some FA-associated genes in the establishment of bona fide FA clinical and cellular phenotypes and excluded FANCM from the group of FA genes (Bogliolo and Surrallés, 2015). The phenotypes associated to FANCM biallelic mutations thus far are cancer predisposition, in particular early-onset breast cancer in females, and chemosensitivity. (Michl et al., 2016; Bogliolo et al., 2017; Catucci et al., 2017).

Here, we have performed a whole-exome sequencing in a Finnish family with two patients presenting with non-syndromic POI and identified a homozygous truncating mutation (c.5101C>T; p.Gln1701*) in FANCM, which explains POI in these patients.

The two POI patients belong to a consanguineous family (Figure 1A) without history of cancer. The parents and the 20 year old brother are reported as healthy, and the mother had regular menses at 47 years. Both patients had normal pilosity, breast and external genitalia, normal blood counts and liver balance, and had normal high-resolution karyotype and FMR1 gene. No abnormalities in skin pigmentation and skeletal development were observed.

Figure 1

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Proband had menarche at 12 years of age, with irregular cycles (20–60 days). Hormonal contraception was started at the age of 16 years for menorrhagia and stopped four years later, after which menstrual cycles became highly irregular (21–140 days). At 24 years, she had hot flushes for about one year and spaniomenorrhea. Blood hormonal assays and ultrasonographic studies of the ovaries are reported in Table 1. FSH level was high (41 IU/l) and AMH low. POI was diagnosed. At the age of 26, hormonal stimulation was attempted with no response. Soon after that, FSH increased to 120 IU/l and hormonal replacement was initiated.

Her sister had menarche at 12 years of age, with regular menses (23 days). Hot flushes started at the age of 20 years. At 22, she consulted for hot flushes and spaniomenorrhea. She had elevated FSH (16 IU/l) and low E2 levels (Table 1). Incipient POI was diagnosed. As prolactin was elevated and brain MRI showed a suspected 3 mm adenoma, treatment with Parlodel was initiated. However, FSH remained elevated and AMH low (Table 1). At 23, hormonal stimulation was initiated with poor results. However, about 6 months later, she became spontaneously pregnant and gave birth to a healthy child.

FANCM is expressed in germ cells of human fetal and adult ovaries

FANCM expression was studied in germ cells of human fetal and adult ovaries. Human fetal material was obtained from the Antoine Béclère Hospital (Clamart, France) following legally-induced abortions or therapeutic termination of pregnancy. The identification of meiotic stages was performed in histological pieces that we have previously characterized (Frydman et al., 2017) and based on the chromatin features. qRT-PCR in human fetal ovaries demonstrated that FANCM mRNAs were expressed throughout ovarian development (5–32 weeks post-fertilization, wpf) (Figure 2A). Of note, expression tended to be higher than average in 14 and 17 wpf ovaries that are stages containing the highest proportion of germ cells progressing into meiotic prophase I.

Figure 2

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Cell-sorting experiments conducted in 8–12 wpf ovaries indicated that FANCM transcripts were predominant in oogonial cells (D2-40-positive) compared to somatic cells (Figure 2B). Immunohistochemical studies in human fetal ovaries show that FANCM protein was present in the nuclei of oogonia but staining was stronger in pachytene stage oocytes (i.e., at 8 and 14 wpf respectively in Figure 2C). Of note, staining localized along the chromosomes in pachytene cells that undergo meiotic recombination. FANCM was also observed in oocytes arrested at the diplotene stage of prophase I during the last trimester of pregnancy and in adults (Figure 2C). The co-staining with Synaptonemal complex protein 3 (SYCP3) or DEAD box protein 4 (DDX4/VASA) confirmed respectively the meiotic and germinal nature of the FANCM-positive cells (Figure 2D).

The FANCM mutation leads to hypersensitivity to Mitomycin C and altered FANCD2 monoubiquitination in response to DNA interstrand crosslinks but not to replication inhibition

Next, we monitored chromosome breakage in primary lymphocytes from the two patients and their mother. Baseline and DNA-damage induced chromosome breakage and rearrangement were blindly scored on 50 metaphases without treatment or after exposure to Mitomycin C (MMC) for 72 hr. In line with a role of FANCM in the maintenance of genome stability, the occurrence of chromosome breakages and rearrangements was higher in both POI patients than in their mother (Figure 3A and B).

Figure 3

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Figure 3—source data 1

File presents the original data of each growth inhibition experiment used to calculate mean and S.D. for Figure 3D.

Numbers are the percentage of cell growth in treated samples compared to the untreated cells. 

https://doi.org/10.7554/eLife.30490.010

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We also determined the impact of the FANCM truncating mutation on the sensitivity to Mitomycin C and on FANCD2 monoubiquitination in response to DNA interstrand crosslinks and replication inhibition. In response to MMC, primary lymphocytes from both patients had a reduced capability to monoubiquitinate FANCD2 (Figure 3C). The reduced level of FANCD2 in lymphocytes from POI patients is likely due to a reduced proliferation of their cells in culture conditions. Next, we determined the growth inhibition response of the lymphoblasts from POI patient-2 and her mother in response to MMC (Figure 3D), as previously described (Ridet et al., 1997). The cells from the mother behaved like FANC-pathway proficient cells, while the response of the mutated cells was similar to that of FANCA- and FANCC-deficient lymphoblasts.

Finally, we assessed FANCD2 monoubiquitination in lymphoblastoid cells in response to MMC, that arrests replication by inducing DNA lesions (Figure 4A), or to two replication inhibitors, hydroxyurea (HU) and aphidicolin (APH), that block replication forks by poisoning DNA polymerases (Figure 4B). Surprisingly, whereas in response to MMC, FANCD2 monoubiquitination was clearly impaired in FANCMmut cells, those cells maintained a residual but detectable capability to monoubiquitinate FANCD2 after HU or APH treatments. Finally, consistent with a proficient DNA damage and stalled replication forks signaling in FANCM mutated cells, we failed to observe any major impairment in the MMC- phosphorylation of H2AX and CHK1 (Figure 4A) (Durocher and Jackson, 2001).

Figure 4

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To further validate that the identified bi-allelic mutation in FANCM was responsible for the MMC hypersensitivity observed in the patient's lymphoblasts, we transduced them with a FANCM-WT cDNA-expressing lentiviral vector (see Materials and methods). Transiently genetically complemented cells recovered a significant resistance to MMC (Figure 3D) as well as an improved monoubiquitination of FANCD2 in response to MMC (Figure 3E).

The two patients with POI studied here belong to a consanguineous family and are thus 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 (first trimester of pregnancy) notably along chromosome axes and increases at the onset of meiosis (second trimester) that are maintained up to the diplotene stage in follicles. Given the known role of FANCM to sustain primordial germ cell proliferation in mouse (Luo et al., 2014) and its conserved function during meiotic recombination (Lorenz et al., 2012; Crismani et al., 2012), it is likely that both processes are sensitive to a FANCM mutation.

FANCM is a nuclear partner of the FANCcore complex, belonging to the FANC pathway that promotes DNA repair and safeguards replication. Indeed, FANCM is targeted to damaged DNA and/or stalled replication forks by its partners FAAP24, FANCM-interacting histone fold protein 1 (MHF1) and 2 (MHF2), where it recruits the FANCcore complex to monoubiquitinate FANCD2 and FANCI and coordinates DNA repair/replication rescue (Ceccaldi et al., 2016; Michl et al., 2016) allowing the faithful transmission of undamaged chromosome to the daughter cells. Consistently, the occurrence of chromosome breakages and rearrangements was higher in both POI patients than in their mother (Figure 3A and B). Our biochemical studies show that lymphocytes from both patients have a reduced capability to monoubiquitinate FANCD2 in response to MMC pointing to a defect in the activation of the FANCcore complex in FANCMmut cells. However the cells maintained a detectable capability to monoubiquitinate FANCD2 in response to HU or APH treatments.

A previous study links POI to other breast cancer genes such as BRCA1 (Oktay et al., 2010). Although recent works established a link between the heterozygous c.5101C>T FANCM truncating mutation and BOC predisposition in the Finnish population (Kiiski et al., 2016, 2014; Neidhardt et al., 2017), there is no history of BOC in the family investigated here. Interestingly, a few apparently healthy (i.e., without cancer) individuals homozygous for the c.5101C>T FANCM mutation were identified in previous studies (Kiiski et al., 2016, 2014; Neidhardt et al., 2017). Indeed, the authors stated, by direct observation or by looking at registered clinical data, that none of them presented FA stigmata (although no data on age, sex or clinical findings was made available). This is in line with the fact that previously identified bi-allelic inactivating FANCM mutations in a few FA patients co-occurred with mutations in other FANC genes, which were indeed responsible for FA (Chang et al., 2014; Singh et al., 2009). This has led to the recent exclusion of FANCM from the group of the bona fide FA genes (Bogliolo and Surrallés, 2015). Very recently two studies report that the phenotypes associated to FANCM biallelic mutations thus far are cancer predisposition, in particular early-onset breast cancer in females, and chemosensitivity (Catucci et al., 2017; Bogliolo et al., 2017). In one study (Catucci et al., 2017), two female patients out of five had premature menopause and one patient had an early reduction of the ovarian reserve according to her AMH levels.

Our results suggest that the cells that harbor biallelic c.5101C>T FANCM mutations maintain a FANCM residual activity allowing them to cope with the stalling of the replication forks during their normal proliferation in vivo, probably protecting individuals from the hematopoietic and developmental abnormalities that constitute the bona fide features of FA. However, the repair defects associated to the c.5101C>T truncating mutation that we describe likely leads to meiotic defects and oocyte apoptosis. Oocytes deficient for DNA repair may accumulate double-strand DNA breaks over time, resulting in reduced oocyte viability (Oktay et al., 2015). Along similar lines, in Fancm^-/- female mice, the ovarian cortex is depleted of primary follicles and the number of developing follicles is reduced compared to WT ovaries. However, due to a bias against Fancm^-/- females, their fertility was not thoroughly investigated (Bakker et al., 2009). Antral follicles were present, albeit in reduced number, which is consistent with the observations in our patients. Some follicles might escape the DNA repair defects and achieve maturation, as epitomized by the presence of antral follicles and corpora lutea in Fancm-deficient mice and by the spontaneous resumption of ovarian function with pregnancy reported in one of our patients. In conclusion, in this report, we document the first case implicating FANCM mutations in non-syndromic POI. Our findings clearly support a genetic link between infertility and DNA-repair/cancer genes and show the necessity to perform an enhanced genetic counseling of POI patients with a long-term follow-up.

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Author details

1. Baptiste Fouquet

   Faculté de Médecine, Université Paris Sud, Université Paris Saclay, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

   Contribution

   Formal analysis, Investigation, Visualization, Writing—original draft, Writing—review and editing

   Contributed equally with

   Patrycja Pawlikowska

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2069-1956

2. Patrycja Pawlikowska

   CNRS UMR8200,Equipe labellisée La Ligue Contre Le Cancer, Université Paris Sud, Université Paris Saclay, Gustave Roussy, Vilejuif, France

   Contribution

   Formal analysis, Investigation, Validation, Visualization

   Contributed equally with

   Baptiste Fouquet

   Competing interests

   No competing interests declared

3. Sandrine Caburet

   Institut Jacques Monod, Université Paris Diderot, Paris, France

   Contribution

   Formal analysis, Visualization, Writing—original draft

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7404-8213

4. Celine Guigon

   Université Paris-Diderot, CNRS, UMR 8251, INSERM, U1133, Paris, France

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

5. Marika Mäkinen

   Department of Clinical Genetics, Turku University Hospital, Turku, Finland

   Contribution

   Resources

   Competing interests

   No competing interests declared

6. Laura Tanner

   Department of Clinical Genetics, Turku University Hospital, Turku, Finland

   Contribution

   Resources

   Competing interests

   No competing interests declared

7. Marja Hietala

   Department of Clinical Genetics, Turku University Hospital, Turku, Finland

   Contribution

   Resources

   Competing interests

   No competing interests declared

8. Kaja Urbanska

   CNRS UMR8200, Université Paris Sud, Université Paris Saclay, Villejuif, France

   Contribution

   Investigation

   Competing interests

   No competing interests declared

9. 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

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

10. Bérangère Legois

    Institut Jacques Monod, Université Paris Diderot, Paris, France

    Contribution

    Formal analysis, Investigation

    Competing interests

    No competing interests declared

11. Bettina Bessieres

    Department of Histology, Embryology and Cytogenetics, Hôpital Necker-enfants malades, Paris, France

    Contribution

    Resources

    Competing interests

    No competing interests declared

12. Alain Gougeon

    UMR Inserm 1052, CNRS 5286, Faculté de Médecine Laennec, Lyon, France

    Contribution

    Resources

    Competing interests

    No competing interests declared

13. Alexandra Benachi

    Department of Obstetrics and Gynaecology, AP-HP, Université Paris-Sud, Université Paris-Saclay, Clamart, France

    Contribution

    Resources

    Competing interests

    No competing interests declared

14. Gabriel Livera

    UMR967 INSERM, CEA/DRF/iRCM/SCSR/LDG, Université Paris Diderot, Sorbonne Paris Cité, Université Paris-Sud, Université Paris-Saclay, Fontenay aux Roses, France

    Contribution

    Formal analysis, Investigation, Writing—original draft

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-8436-4730

15. Filippo Rosselli

    CNRS UMR8200,Equipe labellisée La Ligue Contre Le Cancer, Université Paris Sud, Université Paris Saclay, Gustave Roussy, Vilejuif, France

    Contribution

    Conceptualization, Funding acquisition, Visualization, Methodology, Writing—original draft

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-1080-5745

16. Reiner A Veitia

    Institut Jacques Monod, Université Paris Diderot, Paris, France

    Contribution

    Conceptualization, Formal analysis, Methodology, Writing—original draft, Writing—review and editing

    Contributed equally with

    Micheline Misrahi

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-4100-2681

17. Micheline Misrahi

    Faculté de Médecine, Université Paris Sud, Université Paris Saclay, Hôpital Bicêtre, Le Kremlin-Bicêtre, France

    Contribution

    Conceptualization, Formal analysis, Methodology, Writing—original draft, Writing—review and editing

    Contributed equally with

    Reiner A Veitia

    For correspondence

    Micheline.misrahi@aphp.fr

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-5379-8859

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