Both gain‐of‐function and loss‐of‐function <i>de novo <scp>CACNA</scp>1A</i> mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox‐Gastaut syndrome

Jiang, Xiao; Raju, Praveen Kumar; D’Avanzo, Nazzareno; Lachance, Mathieu; Pepin, Julie; Dubeau, François; Mitchell, Wendy G.; Bello-Espinosa, Luis; Pierson, Tyler Mark; Minassian, Berge A.; Lacaille, Jean-Claude; Rossignol, Elsa

doi:10.1111/epi.16316

Cited by 65 publications

(77 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Patient 1 and patient 2 harbored the same missense variant, C.4055G>A (p.R1352Q), which was reported previously (2, 5-7). The missense variants in patient 4 and patient 5 were C.2137G>A (p.A713T) and C.4177G>A(p.V1393M), respectively, also reported previously (8)(9)(10)(11). Patients 3, 6, and 7 had novel missense variants, C.2102G>T (p.G701V), C.185A>G (p.Y62C), and C.5442T>G (p.F1814L), respectively.…”

Section: Cacna1a Variantssupporting

confidence: 77%

CACNA1A Gene Variants in Eight Chinese Patients With a Wide Range of Phenotypes

et al. 2020

View full text Add to dashboard Cite

Background: The CACNA1A gene encodes the voltage-dependent P/Q-type calcium channel subunit alpha-1A, which is widely expressed throughout the CNS. The biological roles of the P/Q channel are diverse and the phenotypic spectrum caused by CACNA1A mutations is wide. The aim of this study is to demonstrate its phenotypic diversity and analyze the genotype-phenotype correlations in a cohort of Chinese patients.Methods: Patients with hemiplegic migraine, cerebellar ataxia, developmental delay, or epilepsy without known causes were tested by trios whole-exome sequencing. Patients with pathogenic CACNA1A gene variants were recruited. The clinical information of the patients was collected, and the association between the genotype and the phenotype was investigated.Results: In total, eight patients (six females and two males) were found to have CACNA1A gene variants. All the variants were de novo including six missense variants and one frameshift variant. Four de novo missense variants were found in five patients located in the S4, S5, or S6 transmembrane segments of Domain II and III (p.R1352Q, p.G701V, p.A713T, p.V1393M). All of them were correlated with severe phenotypes, including three with sporadic hemiplegic migraine type 1 and epilepsy, and two with developmental and epileptic encephalopathy. The other two missense variants, p.Y62C and p.F1814L, located in the cytoplasmic side of the N-terminus and C-terminus, respectively. The variant p.Y62C was associated with severe hemiconvulsion-hemiplegia-epilepsy syndrome, and p.F1814L was associated with relatively mild phenotypes. All the missense variants were speculated as gain-of-function (GOF) mutations. The only frameshift variant, p.Q681Rfs*100, a lose-of-function (LOF) mutation, was found in a patient with episodic ataxia type 2. Meanwhile, all the patients had developmental delay ranging from mild to severe, as well as cerebellar ataxia including one with congenital ataxia, one with episodic ataxia, and six with non-progressive ataxia.Conclusions:CACNA1A variants could lead to a wide spectrum of neurological disorders including epileptic or non-epileptic paroxysmal events, cerebellar ataxia, and developmental delay. The variants could be both GOF and LOF mutations. There appeared to be some correlations between genotypes and phenotypes.

show abstract

Section: Cacna1a Variantssupporting

confidence: 77%

CACNA1A Gene Variants in Eight Chinese Patients With a Wide Range of Phenotypes

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In addition, Cacna1a S218L mice homozygous for the mutation develop multiple, spontaneous, tonic clonic seizures and die from sudden unexpected death in epilepsy (SUDEP) [48]. Recently, Jiang and colleagues [49], have demonstrated that both gain-and loss-of-function Cacna1a mutations are associated with developmental epileptic encephalopathies.…”

Section: Discussionmentioning

confidence: 99%

Analysis of gene variants in the GASH/Sal model of epilepsy

et al. 2020

View full text Add to dashboard Cite

Epilepsy is a complex neurological disorder characterized by sudden and recurrent seizures, which are caused by various factors, including genetic abnormalities. Several animal models of epilepsy mimic the different symptoms of this disorder. In particular, the genetic audiogenic seizure hamster from Salamanca (GASH/Sal) animals exhibit sound-induced seizures similar to the generalized tonic seizures observed in epileptic patients. However, the genetic alterations underlying the audiogenic seizure susceptibility of the GASH/Sal model remain unknown. In addition, gene variations in the GASH/Sal might have a close resemblance with those described in humans with epilepsy, which is a prerequisite for any new preclinical studies that target genetic abnormalities. Here, we performed whole exome sequencing (WES) in GASH/Sal animals and their corresponding controls to identify and characterize the mutational landscape of the GASH/Sal strain. After filtering the results, moderate-and high-impact variants were validated by Sanger sequencing, assessing the possible impact of the mutations by "in silico" reconstruction of the encoded proteins and analyzing their corresponding biological pathways. Lastly, we quantified gene expression levels by RT-qPCR. In the GASH/Sal model, WES showed the presence of 342 variations, in which 21 were classified as high-impact mutations. After a full bioinformatics analysis to highlight the high quality and reliable variants, the presence of 3 high-impact and 15 moderate-impact variants were identified. Gene expression analysis of the high-impact variants of Asb14 (ankyrin repeat and SOCS Box Containing 14), Msh3 (MutS Homolog 3) and Arh-gef38 (Rho Guanine Nucleotide Exchange Factor 38) genes showed a higher expression in the GASH/Sal than in control hamsters. In silico analysis of the functional consequences indicated that those mutations in the three encoded proteins would have severe functional alterations. By functional analysis of the variants, we detected 44 significantly enriched pathways, including the glutamatergic synapse pathway. The data show three high-impact mutations with a major impact on the function of the proteins encoded by these genes, although no mutation in these three genes has been associated with some type of epilepsy until now. Furthermore, GASH/Sal animals also showed gene variants associated with different types of epilepsy that has been extensively documented, as well as mutations in other genes that PLOS ONE PLOS ONE | https://doi.

show abstract

“…There are also S6 mutations in Cav2.3, the neuronal R-type channel encoded by CACNA1E, that causes developmental and epileptic encephalopathies (DEE) [68]. There is also recent evidence for de novo S6 mutations in CACNA1A, encoding the neuronal P/ Q-type Cav2.1 channel, linked to severe DEE with intellectual disability and variable motor symptoms [78]. All these S6 missense mutations share functional features: they significantly impair the inactivation properties of the affected Cav channels, likely promoting increase in intracellular Ca 2+ concentration and the subsequent cellular damages caused by abnormal Ca 2+ homeostasis [96].…”

Section: Discussionmentioning

confidence: 99%

Neuronal Cav3 channelopathies: recent progress and perspectives

Lory

Nicole

Monteil

2020

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

T-type, low-voltage activated, calcium channels, now designated Cav3 channels, are involved in a wide variety of physiological functions, especially in nervous systems. Their unique electrophysiological properties allow them to finely regulate neuronal excitability and to contribute to sensory processing, sleep, and hormone and neurotransmitter release. In the last two decades, genetic studies, including exploration of knockout mouse models, have greatly contributed to elucidate the role of Cav3 channels in normal physiology, their regulation, and their implication in diseases. Mutations in genes encoding Cav3 channels (CACNA1G, CACNA1H, and CACNA1I) have been linked to a variety of neurodevelopmental, neurological, and psychiatric diseases designated here as neuronal Cav3 channelopathies. In this review, we describe and discuss the clinical findings and supporting in vitro and in vivo studies of the mutant channels, with a focus on de novo, gain-of-function missense mutations recently discovered in CACNA1G and CACNA1H. Overall, the studies of the Cav3 channelopathies help deciphering the pathogenic mechanisms of corresponding diseases and better delineate the properties and physiological roles Cav3 channels.

show abstract

Both gain‐of‐function and loss‐of‐function de novo CACNA1A mutations cause severe developmental epileptic encephalopathies in the spectrum of Lennox‐Gastaut syndrome

Cited by 65 publications

References 50 publications

CACNA1A Gene Variants in Eight Chinese Patients With a Wide Range of Phenotypes

CACNA1A Gene Variants in Eight Chinese Patients With a Wide Range of Phenotypes

Analysis of gene variants in the GASH/Sal model of epilepsy

Neuronal Cav3 channelopathies: recent progress and perspectives

Contact Info

Product

Resources

About