Journal Article

Cav1.2 channelopathies causing autism: new hallmarks on Timothy syndrome

Hidisoglu Enis, Chiantia Giuseppe, Marcantoni, Andrea, Calorio Chiara, Carbone, Emilio

2020

Overview

Cav1.2 L-type calcium channels play key roles in long-term synaptic plasticity, sensory transduction, muscle contraction, and hormone release. De novo mutations in the gene encoding Cav1.2 (CACNA1C) causes two forms of Timothy syndrome (TS1, TS2), characterized by a multisystem disorder inclusive of cardiac arrhythmias, long QT, autism, and adrenal gland dysfunction. In both TS1 and TS2, the missense mutation G406R is on the alternatively spliced exon 8 and 8A coding for the IS6-helix of Cav1.2 and is responsible for the penetrant form of autism in most TS individuals. The mutation causes specific gain-of-function changes to Cav1.2 channel gating: a “leftward shift” of voltage-dependent activation, reduced voltage-dependent inactivation, and a “leftward shift” of steady-state inactivation. How this occurs and how Cav1.2 gating changes alter neuronal firing and synaptic plasticity is still largely unexplained. Trying to better understanding the molecular basis of Cav1.2 gating dysfunctions leading to autism, here, we will present and discuss the properties of recently reported typical and atypical TS phenotypes and the effective gating changes exhibited by missense mutations associated with long QTs without extracardiac symptoms, unrelated to TS. We will also discuss new emerging views achieved from using iPSCs-derived neurons and the newly available autistic TS2-neo mouse model, both appearing promising for understanding neuronal mistuning in autistic TS patients. We will also analyze and describe recent proposals of molecular pathways that might explain mistuned Ca2+-mediated and Ca2+-independent excitation–transcription signals to the nucleus. Briefly, we will also discuss possible pharmacological approaches to treat autism associated with L-type channelopathies.

• Publisher: Springer Nature B.V
• Subject: Adrenal glands / Alternative splicing / Autism / Calcium channels / Calcium channels (L-type) / Calcium channels (voltage-gated) / Calcium signalling / Channel gating / Coding / Hormone release / Inhibitory postsynaptic potentials / Missense mutation / Muscle contraction / Mutation / Phenotypes / Sensory transduction / Synaptic plasticity / Transcription