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Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities

Médéric Jeanne 1, 2 Hélène Demory 1 Aubin Moutal 3 Marie-Laure Vuillaume 1, 2 Sophie Blesson 2 Rose-Anne Thépault 1 Sylviane Marouillat 1 Judith Halewa 1 Saskia M Maas 4 M Mahdi Motazacker 4 Grazia M S Mancini 5 Marjon A van Slegtenhorst 5 Avgi Andreou 6 Helene Cox 6 Julie Vogt 6 Jason Laufman 7 Natella Kostandyan 8 Davit Babikyan 8 Miroslava Hancarova 9 Sarka Bendova 9 Zdenek Sedlacek 9 Kimberly A Aldinger 10 Elliott H Sherr 11 Emanuela Argilli 11 Eleina M England 12 Séverine Audebert-Bellanger 2 Dominique Bonneau 13 Estelle Colin 13 Anne-Sophie Denommé-Pichon 14 Brigitte Gilbert-Dussardier 15 Bertrand Isidor 16 Sebastien Küry 16 Sylvie Odent 17, 18 Richard Redon 16 Rajesh Khanna 3 William B Dobyns 10 Stéphane Bézieau 16 Jérôme Honnorat 19 Bernhard Lohkamp 20 Annick Toutain 1, 2 Frédéric Laumonnier 1, 2, *
Abstract : The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.
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https://hal.archives-ouvertes.fr/hal-03221134
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Soumis le : vendredi 18 juin 2021 - 15:44:26
Dernière modification le : mardi 12 octobre 2021 - 09:30:40
Archivage à long terme le : : dimanche 19 septembre 2021 - 18:51:33

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Médéric Jeanne, Hélène Demory, Aubin Moutal, Marie-Laure Vuillaume, Sophie Blesson, et al.. Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities. American Journal of Human Genetics, Elsevier (Cell Press), 2021, 108 (5), pp.951-961. ⟨10.1016/j.ajhg.2021.04.004⟩. ⟨hal-03221134⟩

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