An autism-causing calcium channel variant functions with selective autophagy to alter axon targeting and behavior

Abstract

Common and rare variants of the CACNA1C voltage-gated calcium channel gene have been associated with autism and other neurodevelopmental disorders including schizophrenia, bipolar disorder and ADHD. However, little is known about how CACNA1C variants affect cellular processes to alter neurodevelopment. The Timothy syndrome mutation is a rare de novo gain-of-function variant in CACNA1C that causes autism with high penetrance, providing a powerful avenue into investigating the role of CACNA1C variants in neurodevelopmental disorders. Here, we use egl-19, the C. elegans homolog of CACNA1C, to investigate the role of voltage-gated calcium channels in autism. We show that an egl-19(gof) mutation that is equivalent to the Timothy syndrome mutation can alter axon targeting and affect behavior in C. elegans. We find that wildtype egl-19 negatively regulates axon termination. The egl-19(gof) mutation represses axon termination to cause axon targeting defects that lead to the misplacement of electrical synapses and alterations in habituation to light touch. Moreover, genetic interactions indicate that the egl-19(gof) mutation functions with genes that promote selective autophagy to cause defects in axon termination and behavior. These results reveal a novel genetic mechanism whereby a de novo mutation in CACNA1C can drive alterations in circuit formation and behavior.

An autism-associated calcium channel variant causes defects in neuronal polarity and axon termination in the ALM neuron ofC. elegans

“…Our previous work demonstrated that PLM axon termination is disrupted by mutations equivalent to the G402R and G406R mutations in CACNA1C (Buddell et al, 2019). Our study also revealed behavioral defects in these mutant worms.…”

Calcium channelopathies and intellectual disability: a systematic review

“…H9C2 and rat myocytes in long QT syndrome type 2 [ 296 ]. Timothy syndrome cardiomyocytes for cardiac arrhythmias [ 174 ] Micro-RNA-137 targets the CACNA1C in mice and human neuroblastoma cells for Alzheimer's disease [ 167 ] MiR-221 and -222 inhibit Cav1.2 current in HL-1 cells [ 168 ] Nifedipine and benidipine hydrochloride inhibited severe fever with thrombocytopenia syndrome in Huh7 cells and in humanized mouse model [ 171 ] MiR-153 inhibitors upregulate the expression of Cacna1c mRNA and protein [ 169 ] Bay K8644 can prevent age related bone loss [ 173 ] MiR-103 can suppress expression of Cav1.2 and thus inhibit osteoblast proliferation [ 170 ] Estradiol can upregulates expression of Cav1.2 [ 148 ] Roscovitine could rescue cardiac arrhythmias [ 174 ] Stac2 and Stac3 can modulate CaV1.2 function [ 175 ] Azelnidipine reduces the expression of Cav1.2 [ 176 ] Wnt pathway for age‐related osteoporosis [ 173 ] Apoptotic pathway in lymphoma [ 172 ] Apoptotic pathway in melanoma [ 192 ] Autophagic pathway in autism [ 197 ] CACNA1D Calcium voltage-gated channel subunit alpha1 D Cav1.3 L-type TsA-201 cells for ID and autism [ 82 , 84 ] TsA-201 cells in hearing [ 297 ]. Rat hippocampal and HEK293 cells for Alzheimer's disease [ 298 ] Isradipine could block Cav1.3 current in vitro [ 84 ] Apoptotic pathway [ 127 ] CACNA1E Calcium voltage-gated channel subunit alpha1 E Cav2.3 R-type TsA201 cells for ID and epilepsy [ 85 ] None Sipatrigine, eugenol, and lamotrigine could block Cav2.3 current [ 177 , …”

“…Cav1.3 current could be blocked by microRNA-107 [ 188 , 189 ] and amlodipine [ 190 ]. The commonest affected pathway is apoptotic pathway [ 127 , 155 , 161 , 172 , 191 – 196 ] followed by autophagic pathway [ 158 , 197 – 199 ], Ras/Raf/MEK-ERK signaling pathway [ 200 – 203 ] and Wnt pathway [ 173 ]. Further details can be found in Table 3 .…”

Update on the Molecular Genetics of Timothy Syndrome

“…No phenotypes were reported in heterozygous animals. One report of an ATS allele in C. elegans identified some axon targeting phenotypes (55) As there are an increasing number of ATS variants, an animal model that is amenable to inexpensive gene editing is needed to test their phenotypic consequences and investigate their mechanisms. Variants of Unknown Significance (VUS) can be verified in such models as well.…”