2. Academic Validation
  3. Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities

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

  • Am J Hum Genet. 2021 May 6;108(5):951-961. doi: 10.1016/j.ajhg.2021.04.004.
Médéric Jeanne 1,  Hélène Demory 2,  Aubin Moutal 3,  Marie-Laure Vuillaume 1,  Sophie Blesson 4,  Rose-Anne Thépault 2,  Sylviane Marouillat 2,  Judith Halewa 2,  Saskia M Maas 5,  M Mahdi Motazacker 6,  Grazia M S Mancini 7,  Marjon A van Slegtenhorst 7,  Avgi Andreou 8,  Helene Cox 8,  Julie Vogt 8,  Jason Laufman 9,  Natella Kostandyan 10,  Davit Babikyan 10,  Miroslava Hancarova 11,  Sarka Bendova 11,  Zdenek Sedlacek 11,  Kimberly A Aldinger 12,  Elliott H Sherr 13,  Emanuela Argilli 13,  Eleina M England 14,  Séverine Audebert-Bellanger 15,  Dominique Bonneau 16,  Estelle Colin 16,  Anne-Sophie Denommé-Pichon 17,  Brigitte Gilbert-Dussardier 18,  Bertrand Isidor 19,  Sébastien Küry 19,  Sylvie Odent 20,  Richard Redon 21,  Rajesh Khanna 3,  William B Dobyns 22,  Stéphane Bézieau 19,  Jérôme Honnorat 23,  Bernhard Lohkamp 24,  Annick Toutain 1,  Frédéric Laumonnier 25
Affiliations

Affiliations

  • 1 UMR 1253, iBrain, Université de Tours, Inserm, 37032 Tours, France; Service de Génétique, Centre Hospitalier Universitaire, 37044 Tours, France.
  • 2 UMR 1253, iBrain, Université de Tours, Inserm, 37032 Tours, France.
  • 3 Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA.
  • 4 Service de Génétique, Centre Hospitalier Universitaire, 37044 Tours, France.
  • 5 Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
  • 6 Department of Clinical Genetics, Laboratory of Genome Diagnostics, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
  • 7 Department of Clinical Genetics, Erasmus MC University Medical Center, 30125 CN Rotterdam, the Netherlands.
  • 8 West Midlands Regional Clinical Genetics Service, Birmingham Women's and Children's Hospital, National Health Service Foundation Trust, Birmingham BT15 2TG, UK; Birmingham Health Partners, Birmingham Women's and Children's Hospital, National Health Service Foundation Trust, Birmingham BT15 2TG, UK.
  • 9 Department of Clinical Genetics, Akron Children's Hospital, Akron, OH 44308-1062, USA.
  • 10 Department of Medical Genetics, Yerevan State Medical University after Mkhitar Heratsi, and Center of Medical Genetics and Primary Health Care, Yerevan 0001, Armenia.
  • 11 Department of Biology and Medical Genetics, Charles University 2(nd) Faculty of Medicine and University Hospital Motol, Charles University, Prague 15006, Czech Republic.
  • 12 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
  • 13 Departments of Neurology and Pediatrics, Weill Institute of Neuroscience and Institute of Human Genetics, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 14 Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 15 Service de Génétique Médicale et de Biologie de la Reproduction, Centre Hospitalier Régional Universitaire, 29200 Brest, France.
  • 16 Department of Biochemistry and Genetics, Angers University Hospital and UMR CNRS 6015-INSERM 1083, University of Angers, 49933 Angers, France.
  • 17 Centre Hospitalier Universitaire de Dijon, UMR Inserm 1231, Team Génétique des Anomalies du Développement, Université de Bourgogne Franche-Comté, 21070 Dijon, France.
  • 18 Service de Génétique, Centre Hospitalier Universitaire, 86021 Poitiers, France; Equipe d'Accueil 3808, Université de Poitiers, 86034 Poitiers, France.
  • 19 Service de Génétique Médicale, Centre Hospitalier Universitaire, 44093 Nantes, France; Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France.
  • 20 Service de Génétique Clinique, Centre Référence Déficiences Intellectuelles de Causes Rares, Centre de Référence Anomalies du Développement, Centre Labellisé pour les Anomalies du Développement Ouest, Centre Hospitalier Universitaire de Rennes, 35203 Rennes, France; Institut de Génétique et Développement de Rennes, CNRS, UMR 6290, Université de Rennes, 35043 Rennes, France.
  • 21 Université de Nantes, CHU Nantes, CNRS, INSERM, l'Institut du Thorax, 44007 Nantes, France.
  • 22 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA 98101, USA; Department of Pediatrics, University of Washington, Seattle, WA 98015, USA.
  • 23 French Reference Center on Autoimmune Encephalitis, Hospices Civils de Lyon, Institut NeuroMyoGene, Inserm U1217/CNRS UMR 5310, Université de Lyon, Université Claude Bernard Lyon 1, 69008 Lyon, France.
  • 24 Division of Molecular Structural Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
  • 25 UMR 1253, iBrain, Université de Tours, Inserm, 37032 Tours, France; Service de Génétique, Centre Hospitalier Universitaire, 37044 Tours, France. Electronic address: [email protected].
PMID: 33894126 DOI: 10.1016/j.ajhg.2021.04.004
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.

Keywords

DPYSL5; brain malformation; corpus callosum agenesis; de novo missense variants; dendrite branching; neurodevelopmental disorder; primary neuronal cultures.

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