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

• DOI: 10.1016/j.ajhg.2021.04.004
• Publication Date: 2021-04-23T14:38:47Z
• Authors: Médéric Jeanne; Hélène Demory; Aubin Moutal; Marie-Laure Vuill...; Sophie Blesson; Rose-Anne Thépault; Sylviane Marouillat; Judith Halewa; Saskia M. Maas; M. Mahdi Motazacker; Grazia M.S. Mancini; Marjon A. van Sle...; Avgi Andreou; Helene Cox; Julie Vogt; Jason Laufman; Natella Kostandyan; Davit Babikyan; Miroslava Hancarova; Sarka Bendova; Zdenek Sedlacek; Kimberly A. Aldinger; Elliott H. Sherr; Emanuela Argilli; Eleina M. England; Séverine Audebert...; Dominique Bonneau; Estelle Colin; Anne-Sophie Denom...; Brigitte Gilbert-...; Bertrand Isidor; Sébastien Küry; Sylvie Odent; Richard Redon; Rajesh Khanna; William B. Dobyns; Stéphane Bézieau; Jérôme Honnorat; Bernhard Lohkamp; Annick Toutain; Frédéric Laumonnier
• Keywords: Male; Models, Molecular; 0301 basic medicine; Biomedical and clinical sciences; Hydrolases; [SDV]Life Sciences [q-bio]; Medical and Health Sciences; Models; Tubulin; Cerebellum; 2.1 Biological and endogenous factors; Aetiology; Child; dendrite branching; de novo missense variants; Pediatric; Genetics & Heredity; DPYSL5; Biological Sciences; corpus callosum agenesis; [SDV] Life Sciences [q-bio]; Biological sciences; Mental Health; Child, Preschool; Neurological; Mental health; Female; Microtubule-Associated Proteins; Adult; Intellectual and Developmental Disabilities (IDD); primary neuronal cultures; Mutation, Missense; Young Adult; 03 medical and health sciences; Rare Diseases; Intellectual Disability; Genetics; Humans; Preschool; Biomedical and Clinical Sciences; brain malformation; Neurosciences; Molecular; Health sciences; neurodevelopmental disorder; Brain Disorders; Neurodevelopmental Disorders; Mutation; Missense; Agenesis of Corpus Callosum

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.