Missense variants in DPYSL5 associated with neurodevelopmental disorders and brain malformations cause impaired neuronal maturation in vitro

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.

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Publication Details

Journal
Molecular Psychiatry
Published
2025-11-24
DOI
https://doi.org/10.1038/s41380-025-03364-8
Citations
1
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
1.82

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article

Missense variants in DPYSL5 associated with neurodevelopmental disorders and brain malformations cause impaired neuronal maturation in vitro

Médéric Jeanne, Frédéric Laumonnier, Camille Kumps, Céline Poirsier et al.
1 citations
Molecular Psychiatry
Genomics and Rare Diseases
1.82
article

Missense variants in DPYSL5 associated with neurodevelopmental disorders and brain malformations cause impaired neuronal maturation in vitro

Médéric Jeanne, Frédéric Laumonnier, Camille Kumps, Céline Poirsier, Joanna Kennedy, Kimberly A. Aldinger, Sylviane Marouillat, Wendy K. Chung, Donald R. Latner, Solène Remizé, Valentin Ruault, Dévina C. Ung, Gaëtan Lesca, Candice R. Finnila, Karen Jaqueline Low, Jean‐Madeleine de Sainte Agathe, Jennifer Cassady Hayek, Sheila Unger, Whitley V. Kelley, Liberty François‐Moutal, Aubin Moutal, Ian A. Glass, Annabelle Tuttle, Florence Desprez, Audrey Dangoumau, Ghayda Mirzaa, Boris Keren, Odile Boute, Sushma N. Guptha
article en
1 citations

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.

Molecular PsychiatryVol. 31(4)
Université Claude Bernard Lyon 1 (FR), Université de Tours (FR), Boston Children's Hospital (US), Centre National de la Recherche Scientifique (FR), Kaiser Permanente (US), Inserm (FR), Université de Montpellier (FR), University of Washington (US), Université de Lille (FR), At Bristol (GB), Centre Hospitalier Universitaire de Lille (FR), University of Bristol (GB), Sorbonne Université (FR), Université Sorbonne Paris Nord (FR), Centre Hospitalier Universitaire de Montpellier (FR), Centre Hospitalier Universitaire de Tours (FR), Assistance Publique – Hôpitaux de Paris (FR), Clinical Investigation Center Plurithematic Tours (FR), Hospices Civils de Lyon (FR), Centre Hospitalier Universitaire de Reims (FR), NIHR Bristol Biomedical Research Centre (GB), Institut NeuroMyoGène (FR), Colorado Permanente Medical Group (US), Brotman Baty Institute (US), HudsonAlpha Institute for Biotechnology (US), Kaiser Permanente San Jose Medical Center (US), Saint Louis University (US), Université de Reims Champagne-Ardenne (FR), University of Lausanne (CH)
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 Percentile: Top 11%
Genomics and Rare Diseases
1.82
DOIOpen Access PDFOpenAlex
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