Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability

Vergult, Sarah; Dheedene, Annelies; Meurs, Alfred; Faes, Franny; Isidor, Bertrand; Janssens, Sandra; Gautier, Agnès; Caignec, Cédric Le; Menten, Björn

doi:10.1038/ejhg.2014.141

Cited by 61 publications

(53 citation statements)

References 39 publications

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“…6c). Using qRT–PCR, we validated the downregulation of ASD-related genes involved in cerebellar development ( Cadps2 and Reln ) (refs 28, 43), and ASD- or epilepsy-related ion channels in neurons ( Cacna2d1 , Grik2 and Kcnd2 ) (refs 43, 44, 45) in ICRF-193 treated or Chd7 mutant CGNs (Fig. 6d,e).…”

Section: Resultsmentioning

confidence: 85%

Chd7 is indispensable for mammalian brain development through activation of a neuronal differentiation programme

et al. 2017

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Mutations in chromatin modifier genes are frequently associated with neurodevelopmental diseases. We herein demonstrate that the chromodomain helicase DNA-binding protein 7 (Chd7), frequently associated with CHARGE syndrome, is indispensable for normal cerebellar development. Genetic inactivation of Chd7 in cerebellar granule neuron progenitors leads to cerebellar hypoplasia in mice, due to the impairment of granule neuron differentiation, induction of apoptosis and abnormal localization of Purkinje cells, which closely recapitulates known clinical features in the cerebella of CHARGE patients. Combinatory molecular analyses reveal that Chd7 is required for the maintenance of open chromatin and thus activation of genes essential for granule neuron differentiation. We further demonstrate that both Chd7 and Top2b are necessary for the transcription of a set of long neuronal genes in cerebellar granule neurons. Altogether, our comprehensive analyses reveal a mechanism with chromatin remodellers governing brain development via controlling a core transcriptional programme for cell-specific differentiation.

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Section: Resultsmentioning

confidence: 85%

Chd7 is indispensable for mammalian brain development through activation of a neuronal differentiation programme

et al. 2017

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“…The collective findings inform pathological mechanisms underlying metabolic disturbances in individuals administered the anti-epileptic and anti-nociceptive drugs gabapentin and pregabalin, which bind and inhibit α 2 δ-1 (DeToledo et al, 1997; Hoppe et al, 2008). They are interesting, considering a recent human study showing that an individual with a de novo chromosomal truncation encompassing CACNA2D1 , the gene encoding α 2 δ-1, exhibited metabolic alterations, including hyperinsulism (Vergult et al, 2014). Because this truncation also involved deletion of the metabolic gene CD36 , the authors speculated that metabolic alterations were elicited by that deficit.…”

Section: Discussionmentioning

confidence: 99%

Alpha2delta-1 in SF1 + Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis

et al. 2017

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SUMMARY The central mechanisms controlling glucose and lipid homeostasis are inadequately understood. We show that α2δ-1 is an essential regulator of glucose and lipid balance, acting in steroidogenic factor-1 (SF1) neurons of the ventromedial hypothalamus (VMH). These effects are body weight independent and involve regulation of SF1+ neuronal activity and sympathetic output to metabolic tissues. Accordingly, mice with α2δ-1 deletion in SF1 neurons exhibit glucose intolerance, altered lipolysis, and decreased cholesterol content in adipose tissue despite normal energy balance regulation. Profound reductions in the firing rate of SF1 neurons, decreased sympathetic output, and elevated circulating levels of serotonin are associated with these alterations. Normal calcium currents but reduced excitatory postsynaptic currents in mutant SF1 neurons implicate α2δ-1 in the promotion of excitatory synaptogenesis separate from its canonical role as a calcium channel subunit. Collectively, these findings identify an essential mechanism that regulates VMH neuronal activity and glycemic and lipid control and may be a target for tackling metabolic disease.

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“…Mutations in CACNA2D2 in humans have been described to cause rare cases of recessive epileptic encephalopathy and mental retardation (Edvardson et al, 2013;Pippucci et al, 2013;Vergult et al, 2015). Family members with one mutated copy of this gene were unaffected.…”

Section: A a 2 D Subunit Genes And Gene Productsmentioning

confidence: 93%

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

Zamponi¹,

Striessnig²,

Koschak³

et al. 2015

Pharmacol Rev

824

898

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Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability

Cited by 61 publications

References 39 publications

Chd7 is indispensable for mammalian brain development through activation of a neuronal differentiation programme

Chd7 is indispensable for mammalian brain development through activation of a neuronal differentiation programme

Alpha2delta-1 in SF1 + Neurons of the Ventromedial Hypothalamus Is an Essential Regulator of Glucose and Lipid Homeostasis

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

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