Key result
Cav1.2 Timothy syndrome mutation drives marked self-injurious scratching despite normal gross brain anatomy in mice.
Why the study?
Timothy Syndrome results from a de novo gain-of-function mutation in Cav1.2 causing cardiac and neurodevelopmental disorders including autism spectrum traits, but its mechanisms remain unclear.
The TS2-NEO mouse model provides a tool for understanding the role of calcium channel inactivation in cardiac function and brain development, despite lacking gross brain anatomical changes.
Highlights behavioral effects of Cav1.2 mutation in mice; leaves open translation to human channelopathies.
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.
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Bett et al. (2012) studied Timothy Syndrome. TS2-NEO knock-in mutation (Cav1.2) vs. Control littermates was evaluated on Cav1.2 isoform expression levels, physical strength, brain anatomy, and self-injurious scratching. Heterozygous TS2-NEO mice with a Cav1.2 mutation survived to reproductive age and exhibited normal gross brain anatomy but a marked propensity towards self-injurious scratching.
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