New CACNA1A deletions are associated to migraine phenotypes

Grieco, Gaetano S.; Gagliardi, Stella; Ricca, Ivana; Pansarasa, Orietta; Neri, Marcella; Gualandi, Francesca; Nappi, Giuseppe; Ferlini, Alessandra; Cereda, Cristina

doi:10.1186/s10194-018-0891-x

Cited by 18 publications

(13 citation statements)

References 21 publications

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“…Multiple genes from this list are linked to neurological conditions. Calcium channel subunits Cacna1d and Cacna1a are associated with autism spectrum disorders 56 and with familial hemiplegic migraine and episodic ataxia 57,58 , respectively. Variants in the Gria4 gene are linked to schizophrenia and intellectual disability [59][60][61] .…”

Section: Loss Of Neat1 Affects Alternative Splicing Of Genes Involvedmentioning

confidence: 99%

Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

Kukharsky

Ninkina

et al. 2020

Transl Psychiatry

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NEAT1 is a highly and ubiquitously expressed long non-coding RNA (lncRNA) which serves as an important regulator of cellular stress response. However, the physiological role of NEAT1 in the central nervous system (CNS) is still poorly understood. In the current study, we addressed this by characterising the CNS function of the Neat1 knockout mouse model (Neat1 −/− mice), using a combination of behavioural phenotyping, electrophysiology and expression analysis. RNAscope® in situ hybridisation revealed that in wild-type mice, Neat1 is expressed across the CNS regions, with high expression in glial cells and low expression in neurons. Loss of Neat1 in mice results in an inadequate reaction to physiological stress manifested as hyperlocomotion and panic escape response. In addition, Neat1 −/− mice display deficits in social interaction and rhythmic patterns of activity but retain normal motor function and memory. Neat1 −/− mice do not present with neuronal loss, overt neuroinflammation or gross synaptic dysfunction in the brain. However, cultured Neat1 −/− neurons are characterised by hyperexcitability and dysregulated calcium homoeostasis, and stressinduced neuronal activity is also augmented in Neat1 −/− mice in vivo. Gene expression analysis showed that Neat1 may act as a weak positive regulator of multiple genes in the brain. Furthermore, loss of Neat1 affects alternative splicing of genes important for the CNS function and implicated in neurological diseases. Overall, our data suggest that Neat1 is involved in stress signalling in the brain and fine-tunes the CNS functions to enable adaptive behaviour in response to physiological stress.

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Section: Loss Of Neat1 Affects Alternative Splicing Of Genes Involvedmentioning

confidence: 99%

Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

Kukharsky

Ninkina

et al. 2020

Transl Psychiatry

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“…In recent years, an increasing number of mutations in the CACNA1A gene have been reported as causative factors for several types of neurological disorders. Using next-generation sequencing, Grieco et al identified an R2157G missense variant in a Moroccan hemiplegic migraine patient and an I1512T missense variation in patients with FHM (6). Using whole-exome sequencing, Khaiboullina et al identified an R583Q missense mutation in patients with FHM (5).…”

Section: Discussionmentioning

confidence: 99%

“…The CACNA1A gene, located on chromosome 19p13, encodes the pore-forming α-1A subunit of human neuronal voltage-gated Cav2.1 (P/Q-type) calcium channels (1,2). Mutations in the CACNA1A gene cause several autosomal-dominant neurological disorders and clinical symptoms/phenotypes such as migraines, spinocerebellar ataxia, familial hemiplegic migraine (FHM), and episodic ataxia (EA) (3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

An elongated tract of polyQ in the carboxyl‑terminus of human α1A calcium channel induces cell apoptosis by nuclear translocation

Sun

et al. 2020

Oncol Rep

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An aberrant elongated tract of glutamine residues (polyQ) in proteins induces multiple diseases treated in the clinic. In our previous study of progressive myoclonic epilepsy (PME), using whole-exome sequencing, a mutant Cav2.1 protein with an aberrant elongated polyQ tract was identified in PME patients. To investigate the molecular mechanism and cell biology of this aberrant elongated polyQ tract, wild-type Cav2.1 with 13 polyQ repeats (Cav2.1 wt-Q13) and mutant-type Cav2.1 with 26 polyQ repeats (Cav2.1 mt-Q26) were prepared and introduced into human SH-SY5Y neuroblastoma cells. Using a WST-1 assay, it was revealed that Cav2.1 mt-Q26 markedly suppressed the proliferation of the SH-SY5Y cells, a result not observed for the Cav2.1 wt-Q13-transfected cells. It was also revealed that Cav2.1 mt and its truncated molecules suppressed cell proliferation by inducing apoptosis rather than arresting the cell cycle. Further investigations indicated a nuclear translocation phenomenon associated with the Cav2.1 mt molecules. Mechanistically, it was revealed that the Cav2.1 mt molecules activated the Bcl-2/Bax, caspase-3 and poly ADP-ribose polymerase (PARP) apoptotic pathways. The present study may provide new insights for interpreting the pathogenesis of PME and the relationship among polyQ, CACNA1A gene mutations and PME.

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“…Multiple genes from this list are linked to neurological conditions. Calcium channel subunits Cacna1d and Cacna1a are associated with autism spectrum disorders (Limpitikul et al, 2016) and with familial hemiplegic migraine and episodic ataxia (Grieco et al, 2018;Jen and Wan, 2018), respectively. Variants in the Gria4 gene are linked to schizophrenia and intellectual disability (Makino et al, 2003;MacDonald et al, 2015;Martin et al, 2017).…”

Section: Loss Of Neat1 Affects Alternative Splicing Of Genes Involvedmentioning

confidence: 99%

Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

Kukharsky

Ninkina

et al. 2019

Preprint

View full text Add to dashboard Cite

NEAT1 is a highly and ubiquitously expressed long non-coding RNA (lncRNA) which serves as an important regulator of cellular stress response. However, the physiological role of NEAT1 in the central nervous system (CNS) is still poorly understood. In the current study, we addressed this by characterising the CNS function in the Neat1 knockout mouse model (Neat1 -/mice), using a combination of behavioural phenotyping, electrophysiology and expression analysis. RNAscope® in situ hybridisation revealed that in wild-type mice, Neat1 is expressed evenly across the CNS, with high expression in glial cells and low expression in neurons. Loss of Neat1 in mice results in an inadequate reaction to physiological stress manifested as hyperlocomotion and panic escape response. In addition, Neat1 -/mice display deficits in social interaction and rhythmic patterns of activity but retain normal motor function and memory. Neat1 -/mice do not present with neuronal loss, overt neuroinflammation or gross synaptic dysfunction in the brain. However, cultured Neat1 -/neurons are characterised by hyperexcitability and dysregulated calcium homeostasis, and stress-induced neuronal activity is also augmented in Neat1 -/mice in vivo. Gene expression analysis showed that Neat1 may act as a weak positive regulator of multiple genes in the brain. Furthermore, loss of Neat1 affects alternative splicing of genes important for the CNS function and implicated in neurological diseases. Overall, our data suggest that Neat1 is involved in stress signaling in the brain and fine-tunes the CNS functions to enable adaptive behaviour in response to physiological stress.

show abstract

New CACNA1A deletions are associated to migraine phenotypes

Cited by 18 publications

References 21 publications

Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

An elongated tract of polyQ in the carboxyl‑terminus of human α1A calcium channel induces cell apoptosis by nuclear translocation

Long non-coding RNA Neat1 regulates adaptive behavioural response to stress in mice

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