A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency
- Faculté de médecine Paris Sud, France
- Université Paris Sud, France
- Université Paris Diderot, France
- Turku University Hospital, Finland
- Hôpital Necker-enfants malades, APHP, France
- Faculté de Médecine Laennec, France
- Cited 1
- Views 806
- Annotations
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 monoubiquitinationFANCM 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.
Article and author information
Author details
Sandrine Caburet
Micheline Misrahi
Funding
Fondation pour la Recherche Médicale (DEQ20150331757)
- Baptiste Fouquet
- Sandrine Caburet
- Reiner A Veitia
- Micheline Misrahi
Ligue Contre le Cancer
- Patrycja Pawlikowska
- Filippo Rosselli
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The study was approved by all the institutions involved. All participants gave informed consent for the study and the study was approved by the agence de Biomedecine (reference number PFS12-002).
Reviewing Editor
- Andrew Deans, Reviewing Editor, St Vincent's Institute of Medical Research, Australia
Publication history
- Received: July 18, 2017
- Accepted: December 11, 2017
- Accepted Manuscript published: December 12, 2017 (version 1)
- Version of Record published: January 11, 2018 (version 2)
Copyright
© 2017, Fouquet et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 806
- Page views
-
- 214
- Downloads
-
- 1
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.
Download links
Downloads (link to download the article as PDF)
Download citations (links to download the citations from this article in formats compatible with various reference manager tools)
Open citations (links to open the citations from this article in various online reference manager services)
Further reading
-
- Genetics and Genomics
- Evolutionary Biology
- Human Biology and Medicine
-
- Human Biology and Medicine
