Mutations in CalDAG-GEFI Lead to Striatal Signaling Deficits and Psychomotor Symptoms in Multiple Species Including Human
Year: 2019
Type: preprint
Abstract: SUMMARY Syndromes caused by mutations in Ras-MAP kinase signaling molecules are known as RASopathies and share features such as developmental delay, autistic traits, and cancer. Syndromic features of Rap-MAP kinase signaling defects remain undefined. CalDAG-GEFI is a calcium-responsive Rap-GTPase activator that is enriched in the matrix of the sensorimotor striatum and down-regulated in Huntington’s disease. We show here that CalDAG-GEFI mutations, including striatum-specific deletions and spontaneous mutations in the enzymatic domain, are associated with psychomotor phenotypes in humans, dogs and mice. The identification of these neural mutants was guided by the overt bleeding phenotype in CalDAG-GEFI knockout mice, and then in humans and other species with conserved platelet signaling deficits. Knockout mice exhibit loss of striatal long-term potentiation and deficits in dopamine, acetylcholine and glutamate signaling, along with delayed motor learning and drug-induced perseverative behaviors. Thus, loss of CalDAG-GEFI signaling produces an evolutionarily conserved syndrome characterized by bleeding and psychomotor dysfunction.
DOI: 10.1101/709246
Authors: Jill R. Crittenden, Magdalena Sauvage, Takashi Kitsukawa, Eric Burguière, Carlos Cepeda, Véronique M. André, Matthias Canault, Morgane Thomsen, Hui Zhang, Cinzia Costa, Giuseppina Martella, Veronica Ghiglieri, Karen A. Pescatore, Ellen M. Unterwald, Walker Jackson, David E. Housman, S. Barak Caine, David Sulzer, Paolo Calabresi, Michael S. Levine, Christine Brefel-Courbon, Anne C. Smith, Marie-Christine Alessi, Jean-Phillipe Azulay, Ann M. Graybiel
Institutions: McGovern Institute for Brain Research, Koch Institute for Integrative Cancer Research At MIT, Massachusetts Institute of Technology, Leibniz Institute for Neurobiology, The University of Osaka, Centre National de la Recherche Scientifique, Inserm, Pitié-Salpêtrière Hospital, Institut du Cerveau, Université Pierre-et-Marie-Curie, University of California, Los Angeles, Aix-Marseille Université, Institut National de la Recherche Agronomique, University of Copenhagen, Harvard University, McLean Hospital, Thomas Jefferson University, New York State Psychiatric Institute, Columbia University, University of Perugia, Fondazione Santa Lucia, Temple University, Linköping University, University of Arizona
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2963344176