title: A Mouse Model of Timothy Syndrome: a Complex Autistic Disorder Resulting from a Point Mutation in Cav1.2.
abstract: Timothy Syndrome (TS) arises from a point mutation in the human voltage-gated L-type Ca2+channel (Cav1.2). TS is associated with cardiac arrhythmias and sudden cardiac death, as well as congenital heart disease, impaired cognitive function, and autism spectrum disorders. TS results from a de novo gain-of-function mutation which affects the voltage dependent component of Cav1.2 inactivation. We created a knock-in TS mouse. No homozygous TS mice survived, but heterozygous TS2-NEO mice (with the mutation and the neocassette in situ) had a normal outward appearance and survived to reproductive age. Previously, we have demonstrated that these mice exhibit the triad of Autistic traits. In this paper we document other aspects of these mice including Cav1.2 isoform expression levels, normal physical strength, brain anatomy and a marked propensity towards self-injurious scratching. Gross brain anatomy was not markedly different in TS2-NEO mice compared to control littermates, and no missing structures were noted. The lack of obvious changes in brain structure is consistent with theTS2-NEO mice may provide a significant tool in understanding the role of calcium channel inactivation in both cardiac function and brain development.
authors.affiliation: Department of Gynecology and Obstetrics, Center for Cellular and Systems Electrophysiology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY ; Department of Physiology and Biophysics, Center for Cellular and Systems Electrophysiology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY.
authors.forename: Glenna Cl
authors.initials: GC
authors.lastname: Bett
authors.affiliation: Department of Physiology and Biophysics, Center for Cellular and Systems Electrophysiology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Lis
authors.affiliation: Department of Psychology, Center for Cellular and Systems Electrophysiology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Wersinger
authors.affiliation: Department of Physiology and Biophysics, Center for Cellular and Systems Electrophysiology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY.
authors.forename: Joan S
authors.initials: JS
authors.lastname: Baizer
authors.affiliation: Department of Physiology and Biophysics, Center for Cellular and Systems Electrophysiology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Duffey
authors.affiliation: Department of Physiology and Biophysics, Center for Cellular and Systems Electrophysiology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY.
authors.forename: Randall L
authors.initials: RL
authors.lastname: Rasmusson
keywords: Autism; brain; calcium; channels; inactivation