RT Journal Article SR Electronic T1 Mutations in CalDAG-GEFI Lead to Striatal Signaling Deficits and Psychomotor Symptoms in Multiple Species Including Human JF bioRxiv FD Cold Spring Harbor Laboratory SP 709246 DO 10.1101/709246 A1 Jill R. Crittenden A1 Magdalena Sauvage A1 Takashi Kitsukawa A1 Eric Burguière A1 Carlos Cepeda A1 Véronique M. André A1 Matthias Canault A1 Morgane Thomsen A1 Hui Zhang A1 Cinzia Costa A1 Giuseppina Martella A1 Veronica Ghiglieri A1 Karen A. Pescatore A1 Ellen M. Unterwald A1 Walker Jackson A1 David E. Housman A1 S. Barak Caine A1 David Sulzer A1 Paolo Calabresi A1 Michael S. Levine A1 Christine Brefel-Courbon A1 Anne C. Smith A1 Marie-Christine Alessi A1 Jean-Phillipe Azulay A1 Ann M. Graybiel YR 2019 UL http://biorxiv.org/content/early/2019/07/22/709246.abstract AB 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.