Dataset Information

Mutation screening of SCN2A in schizophrenia and identification of a novel loss-of-function mutation.

ABSTRACT: OBJECTIVES:There is a growing body of evidence suggesting a shared genetic susceptibility between many neuropsychiatric disorders, including schizophrenia, autism, intellectual disability (ID) and epilepsy. The sodium channel, voltage-gated type II ? subunit gene SCN2A has been shown to exhibit loss-of-function (LoF) mutations in individuals with seizure disorders, ID, autism and schizophrenia. The role of LoF mutations in schizophrenia is still uncertain with only one such mutation identified to date. METHODS:To seek additional evidence for a role for LoF mutations at SCN2A in schizophrenia we performed mutation screening of the entire coding sequence in 980 schizophrenia cases. Given an absence of LoF mutations in a public exome cohort (ESP6500, N=6503), we did not additionally sequence controls. RESULTS:We identified a novel, nonsense (i.e. stop codon) mutation in one case (E169X) that is absent in 4300 European-American and 2203 African-American individuals from the NHLBI Exome Sequencing Project. This is the second LoF allele identified in a schizophrenia case to date. We also show a novel, missense variant, V1282F, that occurs in two cases and is absent in the control dataset. CONCLUSION:We argue that very rare, LoF mutations at SCN2A act in a moderately penetrant manner to increase the risk of developing several neuropsychiatric disorders including seizure disorders, ID, autism and schizophrenia.

SUBMITTER: Carroll LS

PROVIDER: S-EPMC4756433 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mutation screening of SCN2A in schizophrenia and identification of a novel loss-of-function mutation.

Carroll Liam S LS Woolf Rebecca R Ibrahim Yousef Y Williams Hywel J HJ Dwyer Sarah S Walters James J Kirov George G O'Donovan Michael C MC Owen Michael J MJ

Psychiatric genetics 20160401 2

<h4>Objectives</h4>There is a growing body of evidence suggesting a shared genetic susceptibility between many neuropsychiatric disorders, including schizophrenia, autism, intellectual disability (ID) and epilepsy. The sodium channel, voltage-gated type II α subunit gene SCN2A has been shown to exhibit loss-of-function (LoF) mutations in individuals with seizure disorders, ID, autism and schizophrenia. The role of LoF mutations in schizophrenia is still uncertain with only one such mutation iden ...[more]

PMID: 26555645

Similar Datasets

Project description:Short QT syndrome (SQTS) is a genetically determined ion-channel disorder, which may cause malignant tachyarrhythmias and sudden cardiac death. Thus far, mutations in five different genes encoding potassium and calcium channel subunits have been reported. We present, for the first time, a novel loss-of-function mutation coding for an L-type calcium channel subunit.The electrocardiogram of the affected member of a single family revealed a QT interval of 317 ms (QTc 329 ms) with tall, narrow, and symmetrical T-waves. Invasive electrophysiological testing showed short ventricular refractory periods and increased vulnerability to induce ventricular fibrillation. DNA screening of the patient identified no mutation in previously known SQTS genes; however, a new variant at a heterozygous state was identified in the CACNA2D1 gene (nucleotide c.2264G > C; amino acid p.Ser755Thr), coding for the Ca(v)?(2)?-1 subunit of the L-type calcium channel. The pathogenic role of the p.Ser755Thr variant of the CACNA2D1 gene was analysed by using co-expression of the two other L-type calcium channel subunits, Ca(v)1.2?1 and Ca(v)?(2b), in HEK-293 cells. Barium currents (I(Ba)) were recorded in these cells under voltage-clamp conditions using the whole-cell configuration. Co-expression of the p.Ser755Thr Ca(v)?(2)?-1 subunit strongly reduced the I(Ba) by more than 70% when compared with the co-expression of the wild-type (WT) variant. Protein expression of the three subunits was verified by performing western blots of total lysates and cell membrane fractions of HEK-293 cells. The p.Ser755Thr variant of the Ca(v)?(2)?-1 subunit was expressed at a similar level compared with the WT subunit in both fractions. Since the mutant Ca(v)?(2)?-1 subunit did not modify the expression of the pore-forming subunit of the L-type calcium channel, Ca(v)1.2?1, it suggests that single channel biophysical properties of the L-type channel are altered by this variant.In the present study, we report the first pathogenic mutation in the CACNA2D1 gene in humans, which causes a new variant of SQTS. It remains to be determined whether mutations in this gene lead to other manifestations of the J-wave syndrome.

Project description:Mutations in genes coding for subunits of the neuronal nicotinic acetylcholine receptor (nAChR) have been involved in familial sleep-related hypermotor epilepsy (also named autosomal dominant nocturnal frontal lobe epilepsy, ADNFLE). Most of these mutations reside in CHRNA4 and CHRNB2 genes, coding for the α4 and β2 nAChR subunits, respectively. Two mutations with contrasting functional effects were also identified in the CHRNA2 gene coding for the α2 subunit. Here, we report the third mutation in the CHRNA2, found in a patient showing ADNFLE. The patient was examined by scalp EEG, contrast-enhanced brain magnetic resonance imaging (MRI), and nocturnal video-polysomnographic recording. All exons and the exon-intron boundaries of CHRNA2, CHRNA4, CHRNB2, CRH, KCNT1 were amplified and Sanger sequenced. In the proband, we found a c.754T>C (p.Tyr252His) missense mutation located in the N-terminal ligand-binding domain and inherited from the mother. Functional studies were performed by transient co-expression of α2 and α2 Tyr252His , with either β2 or β4, in human embryonic kidney (HEK293) cells. Equimolar amounts of subunits expression were obtained by using F2A-based multi-cistronic constructs encoding for the genes relative to the nAChR subunits of interest and for the enhanced green fluorescent protein. The mutation reduced the maximal currents by approximately 80% in response to saturating concentrations of nicotine in homo- and heterozygous form, in both the α2β4 and α2β2 nAChR subtypes. The effect was accompanied by a strong right-shift of the concentration-response to nicotine. Similar effects were observed using ACh. Negligible effects were produced by α2Tyr252His on the current reversal potential. Moreover, binding of (±)-[3H]Epibatidine revealed an approximately 10-fold decrease of both Kd and Bmax (bound ligand in saturating conditions), in cells expressing α2Tyr252His. The reduced Bmax and whole-cell currents were not caused by a decrease in mutant receptor expression, as minor effects were produced by α2Tyr252His on the level of transcripts and the membrane expression of α2β4 nAChR. Overall, these results suggest that α2Tyr252His strongly reduced the number of channels bound to the agonist, without significantly altering the overall channel expression. We conclude that mutations in CHRNA2 are more commonly linked to ADNFLE than previously thought, and may cause a loss-of-function phenotype.

Dataset Information

Mutation screening of SCN2A in schizophrenia and identification of a novel loss-of-function mutation.

Publications

Mutation screening of SCN2A in schizophrenia and identification of a novel loss-of-function mutation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets