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
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
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).
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.
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A homozygous FANCM mutation underlies a familial case of non-syndromic primary ovarian insufficiency
eLife 6:e30490.
https://doi.org/10.7554/eLife.30490
Further reading
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- Cell Biology
- Medicine
In pulmonary hypertension, a combination of metabolic and mechanical dysfunction leads to irreversible vascular damage.
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- Cell Biology
- Medicine
Background:
Pulmonary vascular remodeling is a progressive pathological process characterized by functional alterations within pulmonary artery smooth muscle cells (PASMCs) and adventitial fibroblasts (PAAFs). Mechanisms driving the transition to a diseased phenotype remain elusive.
Methods:
We combined transcriptomic and proteomic profiling with phenotypic characterization of source-matched cells from healthy controls and individuals with idiopathic pulmonary arterial hypertension (IPAH). Bidirectional cellular crosstalk was examined using direct and indirect co-culture models, and phenotypic responses were assessed via transcriptome analysis.
Results:
PASMC and PAAF undergo distinct phenotypic shifts during pulmonary vascular remodeling, with limited shared features, such as reduced mitochondrial content and hyperpolarization. IPAH-PASMC exhibit increased glycosaminoglycan production and downregulation of contractile machinery, while IPAH-PAAF display a hyperproliferative phenotype. We identified alterations in extracellular matrix components, including laminin and collagen, alongside pentraxin-3 and hepatocyte growth factor, as potential regulators of PASMC phenotypic transitions mediated by PAAF.
Conclusions:
While PASMCs and PAAFs retain their core cellular identities, they acquire distinct disease-associated states. These findings provide new insights into the dynamic interplay of pulmonary vascular mesenchymal cells in disease pathogenesis.
Funding:
This work was supported by Cardio-Pulmonary Institute EXC 2026 390649896 (GK) and Austrian Science Fund (FWF) grant I 4651-B (SC).
