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

Abstract

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.

Two Children with Early-Onset Strokes and Intractable Epilepsy, Both with CACNA1A Mutations

“…Two were diagnosed with Lennox-Gastaut Syndrome, two were diagnosed with Autism Spectrum Disorder, and two developed progressive cerebellar and cerebral atrophy; one experienced nystagmus, one experienced paroxysmal tonic up-gaze, and one experienced a gaze-evoked nystagmus. This mutation was also described in 2 patients by Zhang et al , 12 both of whom experienced early infantile epileptic encephalopathy (EIEE). In a study done by the Epi4K consortium, 7 two patients were found to have this mutation and both experienced convulsive status epilepticus, severe intellectual disability, and early onset epileptic encephalopathy (EOEE).…”

“…7 The specific variant seen in Patient 1 (c.2137 G > A (p.A713T)) is a recurrent, gain-of-function variant that affects the transmembrane S6 segment of Domain II. 12,13 Whole cell recording studies indicate that this mutation in the pore-forming subunit of the Ca v 2.1 channel results in facilitated current activation, slowed current inactivation, and a hyperpolarized shift. 13 Clinically, this variant presents with severe intellectual disability and status epilepticus, with a vast spectrum of other possible clinical findings.…”

Dysregulation of Synaptic Signaling Genes Is Involved in Biology of Uterine Leiomyoma

“…CACNA1A gene encodes the voltage-dependent P/Q-type calcium channel subunit α-1A and is widely expressed throughout the central nervous system. CACNA1A has previously been associated with a wide spectrum of neurological disorders [44]. Additionally, with epigenetic exploration, it was shown that methylation of CACNA1A is one of the markers for irradiation efficacy in oropharyngeal cancer [45].…”

Network-Based Data Analysis Reveals Ion Channel-Related Gene Features in COVID-19: A Bioinformatic Approach

“…Studies have shown that KCNJ4 is associated with the progression and poor prognosis of lung adenocarcinoma (Wu and Yu 2019 ), dilated cardiomyopathy (Szuts et al 2013 ) and prostate cancer (Kim et al 2016 ). The CACNA1A gene encodes a subunit of the voltage-dependent P/Q-type calcium channel α-1A (Zhang et al 2020b ), and the CACNA1E gene encodes a subunit of the voltage-dependent R-type calcium channel α-1E (Helbig et al 2018 ). These genes are widely expressed throughout the central nervous system and are strongly associated with epilepsy and intellectual developmental disorders (Hommersom et al 2021 ; Royer-Bertrand et al 2021 ).…”