Deletions of Cacna2d3 in parvalbumin-expressing neurons leads to autistic-like phenotypes in mice

Shao, Wei; Zheng, Hongxing; Zhu, Jingwen; Li, Wenhao; Li, Yifan; Hu, Wenjie; Zhang, Juanjuan; Liang, Jing; Wang, Kai; Xiao, Jianru

doi:10.1016/j.neuint.2023.105569

Cited by 2 publications

(1 citation statement)

References 73 publications

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“…Disrupting splice site mutation in CACNA2D3 has been found in autism spectrum disorder [ 49 ]. Mice with CACNA2D deletions showed ASD-like phenotype: anxiety, impaired sociability, increased repetitive behavior [ 50 ], and impaired sensory processing through neuronal deficits in the auditory and the acoustic startle pathway [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

Structural Variants and Implicated Processes Associated with Familial Tourette Syndrome

Fichna,

Chiliński,

Halder

et al. 2024

IJMS

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Gilles de la Tourette syndrome (GTS) is a neurodevelopmental psychiatric disorder with complex and elusive etiology with a significant role of genetic factors. The aim of this study was to identify structural variants that could be associated with familial GTS. The study group comprised 17 multiplex families with 80 patients. Structural variants were identified from whole-genome sequencing data and followed by co-segregation and bioinformatic analyses. The localization of these variants was used to select candidate genes and create gene sets, which were subsequently processed in gene ontology and pathway enrichment analysis. Seventy putative pathogenic variants shared among affected individuals within one family but not present in the control group were identified. Only four private or rare deletions were exonic in LDLRAD4, B2M, USH2A, and ZNF765 genes. Notably, the USH2A gene is involved in cochlear development and sensory perception of sound, a process that was associated previously with familial GTS. In addition, two rare variants and three not present in the control group were co-segregating with the disease in two families, and uncommon insertions in GOLM1 and DISC1 were co-segregating in three families each. Enrichment analysis showed that identified structural variants affected synaptic vesicle endocytosis, cell leading-edge organization, and signaling for neurite outgrowth. The results further support the involvement of the regulation of neurotransmission, neuronal migration, and sound-sensing in GTS.

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Section: Discussionmentioning

confidence: 99%

Structural Variants and Implicated Processes Associated with Familial Tourette Syndrome

Fichna,

Chiliński,

Halder

et al. 2024

IJMS

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Autism-Linked Mutations in α2δ-1 and α2δ-3 Reduce Protein Membrane Expression but Affect Neither Calcium Channels nor Trans-Synaptic Signaling

Haddad,

Hessenberger,

Ablinger

et al. 2024

Pharmaceuticals

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Background: α2δ proteins regulate membrane trafficking and biophysical properties of voltage-gated calcium channels. Moreover, they modulate axonal wiring, synapse formation, and trans-synaptic signaling. Several rare missense variants in CACNA2D1 (coding for α2δ-1) and CACNA2D3 (coding for α2δ‑3) genes were identified in patients with autism spectrum disorder (ASD). However, the pathogenicity of these variants is not known, and the molecular mechanism by which α2δ proteins may contribute to the pathophysiology of autism is, as of today, not understood. Therefore, in this study we functionally characterized two heterozygous missense variants in α2δ-1 (p.R351T) and α2δ-3 (p.A275T), previously identified in patients with ASD. Methods: Electrophysiological recordings in transfected tsA201 cells were used to study specific channel-dependent functions of mutated α2δ proteins. Membrane expression, presynaptic targeting, and trans-synaptic signaling of mutated α2δ proteins were studied upon expression in murine cultured hippocampal neurons. Results: Homologous expression of both mutated α2δ proteins revealed a strongly reduced membrane expression and synaptic localization compared to the corresponding wild type α2δ proteins. Moreover, the A275T mutation in α2δ-3 resulted in an altered glycosylation pattern upon heterologous expression. However, neither of the mutations compromised the biophysical properties of postsynaptic L-type (CaV1.2 and CaV1.3) and presynaptic P/Q-type (CaV2.1) channels when co-expressed in tsA201 cells. Furthermore, presynaptic expression of p.R351T in the α2δ-1 splice variant lacking exon 23 did not affect trans-synaptic signaling to postsynaptic GABAA receptors. Conclusions: Our data provide evidence that the pathophysiological mechanisms of ASD-causing mutations of α2δ proteins may not involve their classical channel-dependent and trans-synaptic functions. Alternatively, these mutations may induce subtle changes in synapse formation or neuronal network function, highlighting the need for future α2δ protein-linked disease models.

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Deletions of Cacna2d3 in parvalbumin-expressing neurons leads to autistic-like phenotypes in mice

Cited by 2 publications

References 73 publications

Structural Variants and Implicated Processes Associated with Familial Tourette Syndrome

Structural Variants and Implicated Processes Associated with Familial Tourette Syndrome

Autism-Linked Mutations in α2δ-1 and α2δ-3 Reduce Protein Membrane Expression but Affect Neither Calcium Channels nor Trans-Synaptic Signaling

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