Developmental disorders

Frédéric Ebstein

Investigators: Stéphane Bézieau, Frédéric Ebstein, Sébastien Küry, Bertrand Isidor, Sandra Mercier, Benjamin Cogné
Associated investigators: Wallid Deb, Thomas Besnard, Mathilde Nizon, Marie Vincent
PhD Student : Marielle Oloude
Support staff: Lise Bray, Valeria Dutan-Patino, Yannick Le Dantec, Léa Poirier

Our research team brings together clinical geneticists, researchers and biologists, united by a primary focus on developmental diseases with a particular emphasis on neurodevelopmental disorders, which constitute the primary reason for genetic consultation. Over the past decade, we have successfully identified numerous genes associated with rare genetic conditions, using high-throughput exome or genome sequencing approaches. Recently, we have also integrated transcriptomic approaches into our methodology. Through collaborative investigations on international patient cohorts, we have established genotype-phenotype correlations, significantly advancing our understanding of rare genetic diseases. This effort allowed us to unveil a new category of neurodevelopmental disorders termed ‘neurodevelopmental proteasomopathies’.

Neurodevelopmental proteasomopathies are congenital disorders primarily characterized by impaired neurodevelopment, resulting in manifestations such as speech delay, intellectual disability, motor delay, and behavioral challenges. These disorders stem from alterations in genes related to the proteasome, a multi-subunit protease complex responsible for regulating protein homeostasis within the cell. Over the past five years, our group has made substantial contributions to understanding these disorders, pinpointing three of the four known disease-causing genes. Notably, individuals affected by neurodevelopmental proteasomopathies often exhibit malformations in multiple organ systems, including the face, heart, kidney, skeletal system, and ear. This suggests that proteasome loss-of-function variants primarily impact embryonic precursors involved in the development of cerebral, cardiac, renal, and auditory structures.

Our objective is to assess the influence of proteasome pathogenic variants on the ability of induced pluripotent stem cells (iPSCs) to differentiate into neuronal, craniofacial, and cardiac cellular derivatives and organoids. Our immediate focus is on exploring the transcriptomes, proteomes, and dynamics of proteasome variants in these model systems. Preliminary results indicate that proteasome dysfunction can also be observed in developmental pathologies without neurodevelopmental abnormalities. Some rare genetic diseases are being explored in this context within the team.
 

Learn more about our projects

Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies. Küry, S. et al. Nat. Commun. 16, 10545 (2025).

Ubiquitin-proteasome system dysregulation in FAM111B-related poikiloderma and phenotypic spectrum expansion: new case reports and long-term follow-up.Virginie Vignard, Mike Maillasson, Anne Bigot, Sébastien Küry, Thomas Besnard, Martin Broly, Aurélie Guého, Emmanuelle Com, Erica Davis, Wallid Deb , Laëtitia Florenceau, Karen Sobriel, Grégoire Ménard, Betty Gardie, Alice Goldenberg, Joseph Porrmann, Randal Richardson, Léa Ruffier, Smail Hadj-Rabia, Stéphane Bézieau, Sébastien Barbarot, Frédéric Ebstein, Sandra Mercier, EBioMedicine 119, 105864 (2025).

Dominant variants in major spliceosome U4 and U5 small nuclear RNA genes cause neurodevelopmental disorders through splicing disruption, C Nava, C. Cogné. et al, Nat. Genet. 57, 1374–1388 (2025).

PSMD11 loss-of-function variants correlate with a neurobehavioral phenotype, obesity, and increased interferon response, Deb, W. et al. , . Am. J. Hum. Genet. 111, 1352–1369 (2024).

PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production. F. Ebstein, S. Küry, V. Most, C. Rosenfelt, M.P. Scott-Boyer, G.M. van Woerden, T. Besnard, J.J Papendorf, M. Studencka-Turski, T. Wang, T.C. Hsieh, R. Golnik, D. Baldridge, C. Forster, C. de Konink, S.M.W. Teurlings, V. Vignard, R.H. van Jaarsveld, L. Ades, B. Cogné, C. Mignot, W. Deb, M.C.J. Jongmans, F. Sessions Cole, M.J.H. van den Boogaard, J.A. Wambach, D.J. Wegner, S. Yang, V. Hannig, J.A. Brault, N. Zadeh, B. Bennetts, B. Keren, A.C. Gélineau, Z. Powis, M. Towne, K. Bachman, A. Seeley, A.E. Beck, J. Morrison, R. Westman, K. Averill, T. Brunet, J. Haasters, M.T. Carter, M. Osmond, P.G. Wheeler, F. Forzano, S. Mohammed, Y. Trakadis, A. Accogli, R. Harrison, Y. Guo, H. Hakonarson, S. Rondeau, G. Baujat, G. Barcia, R.G. Feichtinger, J.A. Mayr, M. Preisel, F. Laumonnier, T. Kallinich, A. Knaus, B. Isidor, P. Krawitz, U. Völker, E. Hammer, A. Droit, E.E. Eichler, Y. Elgersma, P.W. Hildebrand, F. Bolduc, E. Krüger and S. Bézieau. Sci Transl Med (2023) May 31
 

Funding

  • ALPHANOSOS
  • Agence nationale de la Recherce
  • CHU de Nantes
  • FHU GenOMedS
  • Fondation Maladies Rares
  • INSERM
  • NExT
  • Région Pays de la Loire



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Updated on 21 July 2026.