TY - JOUR
T1 - Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities
AU - Jeanne, M. déric
AU - Demory, H. lène
AU - Moutal, Aubin
AU - Vuillaume, Marie-Laure
AU - Blesson, Sophie
AU - Thépault, Rose-Anne
AU - Marouillat, Sylviane
AU - Halewa, Judith
AU - Maas, Saskia M.
AU - Motazacker, M. Mahdi
AU - Mancini, Grazia M. S.
AU - van Slegtenhorst, Marjon A.
AU - Andreou, Avgi
AU - Cox, Helene
AU - Vogt, Julie
AU - Laufman, Jason
AU - Kostandyan, Natella
AU - Babikyan, Davit
AU - Hancarova, Miroslava
AU - Bendova, Sarka
AU - Sedlacek, Zdenek
AU - Aldinger, Kimberly A.
AU - Sherr, Elliott H.
AU - Argilli, Emanuela
AU - England, Eleina M.
AU - Audebert-Bellanger, S. verine
AU - Bonneau, Dominique
AU - Colin, Estelle
AU - Denommé-Pichon, Anne-Sophie
AU - Gilbert-Dussardier, Brigitte
AU - Isidor, Bertrand
AU - Küry, S. bastien
AU - Odent, Sylvie
AU - Redon, Richard
AU - Khanna, Rajesh
AU - Dobyns, William B.
AU - Bézieau, Stéphane
AU - Honnorat, J. rôme
AU - Lohkamp, Bernhard
AU - Toutain, Annick
AU - Laumonnier, Frédéric
N1 - Funding Information: We thank the participants and families involved in the study. This work was funded by the Association pour le D?veloppement de la Neurog?n?tique (to F.L.), the Programme Hospitalier de Recherche Clinique Inter-R?gional (grant no. NCT02136849 to S. B?zieau), and the Czech Ministries of Health and Education (grants 17-29423A and LM2018132 to Z.S.). We also thank the IBiSA Electron Microscopy Facility of the University of Tours for management and access to the confocal microscopy platform and the genomics and bioinformatics core facilities of Nantes (GenoBiRD, Biogenouest) for their support to sequencing and data analysis. Exome sequencing and analysis provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) were funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant no. HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant no. WT098051). Funding Information: We thank the participants and families involved in the study. This work was funded by the Association pour le Développement de la Neurogénétique (to F.L.), the Programme Hospitalier de Recherche Clinique Inter-Régional (grant no. NCT02136849 to S. Bézieau), and the Czech Ministries of Health and Education (grants 17-29423A and LM2018132 to Z.S.). We also thank the IBiSA Electron Microscopy Facility of the University of Tours for management and access to the confocal microscopy platform and the genomics and bioinformatics core facilities of Nantes (GenoBiRD, Biogenouest) for their support to sequencing and data analysis. Exome sequencing and analysis provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) were funded by the National Human Genome Research Institute , the National Eye Institute , and the National Heart, Lung, and Blood Institute grant UM1 HG008900 and in part by National Human Genome Research Institute grant R01 HG009141 . The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant no. HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant no. WT098051). Publisher Copyright: © 2021 American Society of Human Genetics Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/5/6
Y1 - 2021/5/6
N2 - 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.
AB - 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.
KW - DPYSL5
KW - brain malformation
KW - corpus callosum agenesis
KW - de novo missense variants
KW - dendrite branching
KW - neurodevelopmental disorder
KW - primary neuronal cultures
UR - http://www.scopus.com/inward/record.url?scp=85105057003&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ajhg.2021.04.004
DO - https://doi.org/10.1016/j.ajhg.2021.04.004
M3 - Article
C2 - 33894126
SN - 0002-9297
VL - 108
SP - 951
EP - 961
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -