Exon–Intron Structure of the Human Neuronal Nicotinic Acetylcholine Receptor α4 Subunit (CHRNA4)

doi:10.1006/geno.1996.0119

Genomics

Volume 32, Issue 2, 1 March 1996, Pages 289-294

https://doi.org/10.1006/geno.1996.0119 Get rights and content

Abstract

The human neuronal nicotinic acetylcholine receptor α4 subunit gene (CHRNA4) is located in the candidate region for three different phenotypes: benign familial neonatal convulsions, autosomal dominant nocturnal frontal lobe epilepsy, and low-voltage EEG. Recently, a missense mutation in transmembrane domain 2 of CHRNA4 was found to be associated with autosomal dominant nocturnal frontal lobe epilepsy in one extended pedigree. We have determined the genomic organization of CHRNA4, which consists of six exons distributed over approximately 17 kb of genomic DNA. The nucleotide sequence obtained from the genomic regions adjacent to the exon boundaries enabled us to develop a set of primer pairs for PCR amplification of the complete coding region. The sequence analysis provides the basis for a comprehensive mutation screening of CHRNA4 in the above-mentioned phenotypes and possibly in other types of idiopathic epilepsies.

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Cited by (50)

Autosomal dominant sleep-related hypermotor epilepsy caused by a previously unreported CHRNA4 variant
2022, European Journal of Medical Genetics
Citation Excerpt :
Regardless of location, pathogenic variants in CHRNA4 that have undergone functional studies, have been predicted to have a gain-of-function effect, increasing the activity of the receptor (Steinlein et al., 2012). Val330Met is located in the transition from TM3 to C2 in vicinity to two already reported variants p.Val327Met located in TM3 and p.Arg336His located in C2 (Steinlein et al., 1996; Chen et al., 2009; Jiang et al., 2018). The genetic and phenotypic picture of this family is complex.
Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is a rare heritable form of epilepsy. It is characterized by hypermotor seizures occurring mainly during sleep. Seizures are typically abrupt in onset and offset and tend to increase in complexity and duration during the night.
ADSHE is inherited in an autosomal dominant manner, and penetrance is estimated to be 70%. We describe two brothers with ADSHE with a previously unreported variant in CHRNA4, and the effect of medical treatment with carbamazepine. We highlight the relevance of genetic testing in patients with atypical and clustering episodes of nightmares, night terrors, or panic attacks, as these patients could be misdiagnosed, and instead be suffering from ADSHE, a potentially treatable condition.
α-4 subunit of nicotinic acetylcholine receptor polymorphisms exhibit no association with smoking behavior among Malay Males in Kelantan, Malaysia
2016, Egyptian Journal of Medical Human Genetics
Citation Excerpt :
According to Tapper et al. [22] α-4 subunit of nicotinic acetylcholine receptor (CHRNA4) is the most important for nicotine-induced reward, tolerance, as well as sensitization. The CHRNA4 gene, which was mapped to chromosome 20q13.2–13.3 is 17 kb long and contains six exons [23]. Therefore, the gene encoding this subunit can be considered as a good candidate gene for smoking behavior.
Smoking behavior is influenced by both genetic and environmental factors. Nicotine is the major addictive substance in cigarettes. Nicotinic acetylcholine receptors (nAChRs) are thought to play an important role in nicotine addiction of smokers. One of the genes, α-4 subunit of nicotinic acetylcholine receptor (CHRNA4) gene was reported to be associated with smoking behavior in many populations.
The aim of this study is to determine association between α-4 subunit of nicotinic acetylcholine receptor single nucleotide polymorphism (rs2236196 and rs2273502 loci) and smoking behavior among Malay Males.
The study was conducted in Malay smokers (n = 248) and non-smoking controls (n = 248). DNA was extracted from leucocytes and the two SNPs were determined by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The PCR product was digested with restriction enzymes AfeI and Sau96I, respectively.
We found that the AA genotype frequency for CHRNA4 rs2236196 polymorphism in the smoker group was 80.6% while in nonsmoker 77.0%. No mutation (GG genotype) was detected in both groups. The AG genotype for the smoker group was 19.4% while in the nonsmoker group 23.0%. There was no significant difference observed in the genotype (χ² = 5.106, p = 0.078) and allele frequencies between both study groups. On the other hand, no mutation of CHRNA4 rs2273502 (TT genotype) was detected in the non-smoker group while the frequencies of genotype CC and heterozygous CT in non-smokers were 75.8% and 24.2%, respectively. In the smoker group, the frequencies were 73.4%, 2.0% and 24.6%, for TT, CC and CT, respectively. There was no significant difference observed in rs2273502 (χ² = 5.16, p = 0.078) and smoking behavior of the subjects. In conclusion, the results revealed that CHRNA4 rs2273502 and rs2236196 gene polymorphisms are not statistically significantly associated with smoking behavior in our population.
The genetics of monogenic idiopathic epilepsies and epileptic encephalopathies
2012, Seizure
Citation Excerpt :
The estimated penetrance is 70%. Mutations in CHRNA4, CHRNB2, or CHRNA2, which encode the neuronal acetylcholine receptor (α4, β2, and α2 subunit, respectively) can be found in around 10–20% of the individuals with a positive family history but only in around 5% of the individuals with a negative family history.124–127 The pore-forming M2 transmembrane segments are affected by these mutations, and increased acetylcholine sensitivity is believed to be the main defect of the mutation.1
The group of idiopathic epilepsies encompasses numerous syndromes without known organic substrate. Genetic anomalies are thought to be responsible for pathogenesis, with a monogenic or polygenic model of inheritance. Over the last two decades, a number of genetic anomalies and encoded proteins have been related to particular idiopathic epilepsies and epileptic encephalopathies. Most of these mutations involve subunits of neuronal ion channels (e.g. potassium, sodium, and chloride channels), and may result in abnormal neuronal hyperexcitability manifesting with seizures. However non-ion channel proteins may also be affected. Correlations between genotype and phenotype are not easy to establish, since genetic and non-genetic factors are likely to play a role in determining the severity of clinical features. The growing number of discoveries on this topic are improving classification, prognosis and counseling of patients and families with these forms of epilepsy, and may lead to targeted therapeutic approaches in the near future. In this article the authors have reviewed the main genetic discoveries in the field of the monogenic idiopathic epilepsies and epileptic encephalopathies, in order to provide epileptologists with a concise and comprehensive summary of clinical and genetic features of these seizure disorders.
Nicotinic Acetylcholine Receptor α4 Subunit Gene Variation Associated with Attention Deficit Hyperactivity Disorder
2009, Tsinghua Science and Technology
Previous pharmacological, human genetics, and animal models have implicated the nicotinic acetylcholine receptor α4 subunit (CHRNA4) gene in the pathogenesis of attention deficit/hyperactivity disorder (ADHD). The objective of this study is to examine the genetic association between single nucleotide polymorphisms in the CHRNA4 gene (rs2273502, rs1044396, rs1044397, and rs3827020 loci) and ADHD. Both case-control and family-based designs are used. Children aged 6 to 16 years were interviewed and assessed with the children behavior checklist and the revised conner' parent rating scale to identify probands. No significant differences in the frequency distribution of genotypes or alleles were found between the case and control groups. However, further haplotype analyses showed the CCGG haplotype on risk for ADHD in 164 case-control samples and the standard transmission disequilibrium test analyses suggest that the allele C of rs2273502 was over-transferred in 98 ADHD parent-offspring trios. These findings suggest that the CHRNA4 gene may play a role in the pathogenesis of ADHD.
A novel mutation of the nicotinic acetylcholine receptor gene CHRNA4 in sporadic nocturnal frontal lobe epilepsy
2009, Epilepsy Research
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is known to be partly caused by mutations in the transmembrane domain (TM) 1-3 of the genes of the neuronal nicotinic acetylcholine receptor (nAChR) α4-subunit (CHRNA4), β2-subunit (CHRNB2) and α2-subunit (CHRNA2). The more common cases of sporadic nocturnal frontal lobe epilepsy (NFLE) that are not differentiated from ADNFLE by phenotype have been found to be associated with the mutation of CHRNA4 reported in ADNFLE. In order to assess the genetic defects in NFLE, we performed a mutation screening in 33 unrelated patients with sporadic NFLE by amplifying and sequencing bidirectionally TM 1-3 of CHRNA4, CHRNB2 and CHRNA2 which contain the mutations reported in ADNFLE. In screening CHRNA4, we identified a novel mutation in one patient that causes a α4-R308H amino acid exchange outside the TM, and in the second intracellular loop between the third and fourth transmembrane domains. The mutation was not observed in 400 control chromosomes. No mutations were present in parts of CHRNB2 and CHRNA2.
Epilepsy predisposition and pharmacogenetics
2009, Genomic and Personalized Medicine, Two-Vol Set

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Short CommunicationExon–Intron Structure of the Human Neuronal Nicotinic Acetylcholine Receptor α4 Subunit (CHRNA4)

Abstract

Short Communication
Exon–Intron Structure of the Human Neuronal Nicotinic Acetylcholine Receptor α4 Subunit (CHRNA4)