Contribution of CACNA1H Variants in Autism Spectrum Disorder Susceptibility

Abstract

Autism Spectrum Disorder (ASD) is a highly heterogeneous neuropsychiatric disorder with a strong genetic component. The genetic architecture is complex, consisting of a combination of common low-risk and more penetrant rare variants. Voltage-gated calcium channels (VGCCs or Cav) genes have been implicated as high-confidence susceptibility genes for ASD, in accordance with the relevant role of calcium signaling in neuronal function. In order to further investigate the involvement of VGCCs rare variants in ASD susceptibility, we performed whole genome sequencing analysis in a cohort of 105 families, composed of 124 ASD individuals, 210 parents and 58 unaffected siblings. We identified 53 rare inherited damaging variants in Cav genes, including genes coding for the principal subunit and genes coding for the auxiliary subunits, in 40 ASD families. Interestingly, biallelic rare damaging missense variants were detected in the CACNA1H gene, coding for the T-type Cav3.2 channel, in ASD probands from two different families. Thus, to clarify the role of these CACNA1H variants on calcium channel activity we performed electrophysiological analysis using whole-cell patch clamp technology. Three out of four tested variants were shown to mildly affect Cav3.2 channel current density and activation properties, possibly leading to a dysregulation of intracellular Ca2+ ions homeostasis, thus altering calcium-dependent neuronal processes and contributing to ASD etiology in these families. Our results provide further support for the role of CACNA1H in neurodevelopmental disorders and suggest that rare CACNA1H variants may be involved in ASD development, providing a high-risk genetic background.

Increased NMDARs in neurons and glutamine synthetase in astrocytes underlying autistic-like behaviors of Gabrb1−/− mice

“…The genomic abnormalities of Cacna1h and Kdm5c are reported to associate with ASD. 50 , 51 The CACNA1H gene encodes the calcium channel Cav 3.2 in excitable cells, regulating intracellular calcium concentration. 28 The upregulation of Cacna1h in Gabrb1 −/− mice might contribute to the neurotransmitter release in glutamatergic neurons.…”

Simultaneous CRISPR screening and spatial transcriptomics reveals intracellular, intercellular, and functional transcriptional circuits

“…Several publications have highlighted transcriptional differences within astrocytes between ASD patients and control groups [33][34][35] . There have also been reports of a functional role of calcium activity in the development of ASD symptoms [36][37][38] , specifically that ASD patient iPS-derived astrocytes show aberrant calcium activity and that injecting these cells into healthy mice is enough to generate ASD like behaviors 39 ; or that disrupting calcium activity in astrocytes generates ASD like behaviors in mice 38 . We thus decided to explore the power of Perturb-FISH to study a new biological problem by determining if a set of ASD risk genes with largely unknown roles converge on aberrant calcium signaling in iPS-derived astrocytes.…”

Genetic ablation of metabotropic glutamate receptor 5 in rats results in an autism-like behavioral phenotype

“…Although the exact etiology of ASD remains an enigma, at least 30% of cases have an underlying genetic etiology [28][29][30][31][32][33][34][35]. The most common gene variants involved in ASD include SHANK3, MECP2, NLGN3, NRXN1 and FMR1 [36][37][38][39][40][41][42][43][44][45][46][47][48][49][50], some of which are regulated by the metabotropic glutamate receptor (mGluR) pathway, especially mGluR5, thus making it a very attractive target for understanding the pathogenesis of ASD [51].…”