Missense variants in DPYSL5 associated with neurodevelopmental disorders and brain malformations cause impaired neuronal maturation in vitro
Year: 2025
Type: article
Abstract: Neurodevelopmental disorders (NDD) with brain malformations have recently been associated with de novo variants in the DPYSL5 gene, which encodes a member of the dihydropyrimidinase-like proteins family. Here, we aimed to understand its role in NDD by characterizing novel or recurrent de novo variants at the molecular and cellular levels. We collected clinical data on individuals in whom DPYSL5 missense variants were identified through clinical genetic assessment of NDD or following the identification of brain malformations in fetuses. Functional analyses of wild-type and variant DPYSL5 proteins were performed to evaluate their impact on in vitro neuronal development and maturation, using primary neuronal cultures from mouse embryonic brains or hiPSC-derived human neural stem cells. We describe six different missense variants in DPYSL5 in nine individuals (including three fetuses), including the previously identified p.(Glu41Lys) recurrent mutation (in 2 individuals), a novel recurrent missense p.(Glu25Lys) de novo variant (in 3 individuals including 2 fetuses), and 3 novel candidates. Common features were developmental delay, intellectual disability, as well as brain malformations including agenesis of the corpus callosum for the N-terminal variants. Functional assays in differentiating mouse or human neuronal cultures revealed impairments in dendritic arborization, axonal elongation, and synaptic density. We thus expanded the functional characterization of DPYSL5 variants in NDD with brain malformations, including at the fetal stage, highlighting a fundamental role of the DPYSL5 gene in brain formation and functioning.
Source: Molecular Psychiatry
Authors: Florence Desprez, Solène Remize, Liberty François-Moutal, Dévina C. Ung, Audrey Dangoumau, Sylviane Marouillat, Joanna Kennedy, Karen J. Low, Camille Kumps, Sheila Unger, Boris Keren, Jean-Madeleine de Sainte Agathe, Céline Poirsier, Ghayda M. Mirzaa, Kimberly A. Aldinger, Gaetan Lesca, Valentin Ruault, Candice R. Finnila, Whitley V. Kelley, Donald R. Latner, Sushma N. Guptha, Annabelle Tuttle, Ian Glass, Wendy K. Chung, Jennifer Cassady Hayek, Odile Boute, Aubin Moutal, Médéric Jeanne, Frédéric Laumonnier
Institutions: Université de Tours, Inserm, Imaging, Brain, and Neuropsychiatry, Centre Hospitalier Universitaire de Tours, Saint Louis University, University Hospitals Bristol NHS Foundation Trust, University of Bristol, Centre Hospitalier Universitaire Vaudois, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Centre Hospitalier Universitaire de Reims, University of Washington, Brotman Baty Institute, Seattle Children's Research Institute, Lyon 1 Université, Centre National de la Recherche Scientifique, Hospices Civils de Lyon, Laboratoire Physiopathologie et Génétique du Neurone et du Muscle, Centre Hospitalier Universitaire de Montpellier, HudsonAlpha Institute for Biotechnology, Kaiser Permanente San Jose Medical Center, Boston Children's Hospital, Harvard University, Université de Lille, Centre Hospitalier Universitaire de Lille, Maladies RAres du DEveloppement embryonnaire et du MEtabolisme
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,490
Funders: Saint Louis University, Infrastructures en Biologie Santé et Agronomie, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Université François-Rabelais, National Institutes of Health, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke
OpenAlex ID: W4416602836