Molecular Oncology and Ovarian Pathologies
Our team focuses on the study of ovarian development and function through molecular genetics. Our research is carried out through the molecular analysis of different pathologies such as the blepharophimosis syndrome, premature ovarian insufficiency (POI) or granulosa cell tumors, affecting one of the somatic cell types of the ovary. One of the historical topics of the group is the analysis of the blepharophimosis syndrome, involving craniofacial anomalies and POI, due to alterations in the transcription factor (TF) FOXL2. Over the years, we have contributed to a better understanding of its molecular function, pathogenic mechanisms, targets and partners. We use FOXL2 as a model to explore the basis of the specific recognition of a target by a TF and the influence of partners and post-translational modifications in this process. We are also investigating the involvement of FOXL2 in adult granulosa cell tumors (AGCT). Indeed, a recurrent somatic mutation in FOXL2, leading to the p.C134W substitution has been detected in more than 97% of AGCTs, suggesting that this mutation is a key element (driver) in their formation. We are actively studying the pathogenic mechanisms of this mutation using CRISPR-Cas9 modified cell lines, an animal model and genomic tools. For the juvenile form of GCTs, we have recently reported the presence of insertions in the AKT1 oncogene that are likely responsible for the tumors, paving the way for further research. Finally, we are taking advantage of the power of current genomic technology to perform exome sequencing in familial and isolated cases of POI to uncover genes whose mutations are responsible for this condition. We have thus shown the involvement in POI of genes such as STAG3 or more recently MEIOB.
Group Leader: Reiner A. VEITIA
Professor of Genetics, University of Paris
Veitia RA, Pilsworth J, Todeschini AL, Huntsman D.EMBO J. 2021 Aug 16;40(16):e107517. doi: 10.15252/embj.2020107517.PMID: 34396573
FOXL2 in adult-type granulosa cell tumour of the ovary: oncogene or tumour suppressor gene? Pilsworth JA, Todeschini AL, Neilson SJ, Cochrane DR, Lai D, Anttonen M, Heikinheimo M, Huntsman DG, Veitia RA.J Pathol. 2021 Nov;255(3):225-231. doi: 10.1002/path.5771. Epub 2021 Sep 1.PMID: 34338304
Insights into the pathogenicity of missense variants in the forkhead domain of FOX proteins underlying Mendelian disorders. Bermúdez-Guzmán L, Veitia RA. Hum Genet. 2021 Jul;140(7):999-1010.
Forkhead Transcription Factors in Health and Disease. Herman L, Todeschini AL, Veitia RA.Trends Genet. 2021 May;37(5):460-475 (Review).
Genomic exploration of the targets of FOXL2 and ESR2 unveils their implication in cell migration, invasion, and adhesion. Herman L, Legois B, Todeschini AL, Veitia RA.FASEB J. 2021 Apr;35(4):e21355. doi: 10.1096/fj.202002444R.PMID: 33749886
A missense in HSF2BP causing primary ovarian insufficiency affects meiotic recombination by its novel interactor C19ORF57/BRME1. Felipe-Medina N, Caburet S, Sánchez-Sáez F, Condezo YB, de Rooij DG, Gómez-H L, Garcia-Valiente R, Todeschini AL, Duque P, Sánchez-Martin MA, Shalev SA, Llano E, Veitia RA, Pendás AM.Elife. 2020 Aug 26;9:e56996. doi: 10.7554/eLife.56996.PMID: 32845237 Free
An exome-wide exploration of cases of primary ovarian insufficiency uncovers novel sequence variants and candidate genes. Alvarez-Mora MI, Todeschini AL, Caburet S, Perets LP, Mila M, Younis JS, Shalev S, Veitia RA.Clin Genet. 2020 Sep;98(3):293-298. doi: 10.1111/cge.13803. Epub 2020 Jul 28.PMID: 32613604
DHH pathogenic variants involved in 46,XY disorders of sex development differentially impact protein self-cleavage and structural conformation. Elzaiat M, Flatters D, Sierra-Díaz DC, Legois B, Laissue P, Veitia RA.Hum Genet. 2020 Nov;139(11):1455-1470.
Conventional and unconventional interactions of the transcription factor FOXL2 uncovered by a proteome-wide analysis. Penrad-Mobayed M, Perrin C, Herman L, Todeschini AL, Nigon F, Cosson B, Caburet S, Veitia RA.FASEB J. 2020 Jan;34(1):571-587. doi: 10.1096/fj.201901573R. Epub 2019 Nov 25.PMID: 31914586
Caburet S, Todeschini AL, Petrillo C, Martini E, Farran ND, Legois B, Livera G, Younis JS, Shalev S, Veitia RA.EBioMedicine. 2019 Apr;42:524-531. doi: 10.1016/j.ebiom.2019.03.075. Epub 2019 Apr 15.PMID: 31000419