Disease relevance of CHRNA4

• Autosomal dominant nocturnal frontal-lobe epilepsy (ADNFLE) is a recently identified partial epilepsy in which two different mutations have been described in the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4) [1].
• The human neuronal nicotinic acetylcholine receptor alpha 4 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 [2].
• CHRNA4 led the way to mutation identifications in 15 ion channel genes, most causing primarily generalized epilepsies [3].
• A genetically determined generalized hyperexcitability had been predicted in primarily generalized seizures, but surprisingly the first epilepsy gene discovered, CHRNA4, was in a focal (frontal lobe)-onset syndrome [4].
• In the present study, we examined the possible role of CHRNA4 in common subtypes of idiopathic generalized epilepsy (IGE), comprising childhood and juvenile absence epilepsy and juvenile myoclonic epilepsy (JME), by systematically screening the coding region of the gene for sequence variants [5].

Psychiatry related information on CHRNA4

• Two clinically distinct phenotypes may be drawn, a mild mental retardation or a more complex and severe phenotype, according to the presence or absence of the CHRNA4 and ARFGAP1 genes respectively.European Journal of Human Genetics (2007) 15, 446-452. doi:10.1038/sj.ejhg.5201784; published online 7 February 2007 [6].
• This study does not support an association between panic disorder and the CHRNA4 gene [7].
• Mutation screening of the CHRNA4 and CHRNB2 nicotinic cholinergic receptor genes in Alzheimer's disease [8].
• Both CHRNA4 polymorphisms and the extent of dementia seem to affect the levels of DNA oxidative damage as well as to activate factors that participate in the DNA degradation and its repair [9].
• Increasing gene dose of the C allele of the CHRNA4 gene (i.e., no C alleles, one C allele, two C alleles) was associated with increased reaction time (RT) benefits of valid attentional cuing and reduced RT costs of invalid cues, but was not associated with working memory performance [10].

High impact information on CHRNA4

• The neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) maps to the same region of 20q (ref. 12) and the gene is expressed in all layers of the frontal cortex [11].
• We screened affected family members for mutations within CHRNA4 and found a missense mutation that replaces serine with phenylalanine at codon 248, a strongly conserved amino acid residue in the second transmembrane domain [11].
• Compared with the CHRNA4 and CHRNB2 mutations reported elsewhere, CHRNA2 mutations cause a more complex and finalized ictal behavior [12].
• Our findings provide strong evidence suggesting a common CHRNA4 haplotype might be protective against vulnerability to nicotine addiction in men [13].
• An additional seven families are presented in which ADNFLE is unlinked to the CHRNA4 region on chromosome 20q13 [1].

Biological context of CHRNA4

• Recombination between ADNFLE and CHRNA4, linkage to 15q24 in one family, and exclusion from 15q24 and 20q13.2 in others demonstrate genetic heterogeneity with at least three different genes for ADNFLE [1].
• We studied six single-nucleotide polymorphisms (SNPs) in the CHRNA4 gene and four SNPs in the CHRNB2 gene with respect to nicotine dependence in a collection of 901 subjects (815 siblings and 86 parents) from 222 nuclear families with multiple nicotine-addicted siblings [13].
• Exon 5 of CHRNA4 and CHRNB2 genes, harboring all the known mutations, was sequenced in the probands [14].
• We have utilized Southern blot analysis on human/rodent somatic cell hybrids to map the human homologues of both of these genes, PCK1 and CHRNA4, to human chromosome 20 [15].
• We were able to detect the association between the CfoI polymorphism of the CHRNA4 and alcoholism in Korean patients (genotype P = .023; allele frequency P = .047) [16].

Anatomical context of CHRNA4

• Understanding of the molecular basis of paroxysmal disorders affecting the central nervous system has been revolutionalized with the identification of mutations in genes for the neurotransmitter receptors, GLRA1 and CHRNA4, and a voltage-gated potassium channel, KCNA1, as causes of inherited neurological disease [17].
• Once a CHRNA4 mutation was identified, its biophysical and pharmacologic properties were characterized by expression experiments in Xenopus oocytes [18].
• Polymorphisms of the CHRNA4 gene encoding the alpha4 subunit of nicotinic acetylcholine receptor as related to the oxidative DNA damage and the level of apoptotic proteins in lymphocytes of the patients with Alzheimer's disease [9].

Associations of CHRNA4 with chemical compounds

• Because this gene (CHRNA4) codes for a neuronal nicotinic acetylcholine receptor subunit, functional studies could be designed to evaluate the alterations caused by this mutation [19].
• Association of polymorphisms in nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4), mu-opioid receptor gene (OPRM1), and ethanol-metabolizing enzyme genes with alcoholism in Korean patients [16].
• C755T replaced serine 252 (Ser252) in the second membrane-spanning domain (M2) of CHRNA4 with a leucine [20].

Physical interactions of CHRNA4

• APOE interacted with CHRNA4, such that APOE-epsilon4 carriers who were also CHRNA4 TT homozygotes showed disproportionately slowed reaction time (RT) following invalid location cues [21].

Regulatory relationships of CHRNA4

• The missense mutation (Ser248Phe), associated with ADNFLE, and four silent polymorphisms in the CHRNA4 gene were genotyped in 103 IGE patients and 92 controls by polymerase chain reaction and subsequent restriction analysis [5].

Other interactions of CHRNA4

• Six polymorphic microsatellite markers covering the BFIC locus on chromosomal region 19q, one marker for CHRNA4 (chromosome 20) and two for CHRNA7 (chromosome 15) were used for the screening [22].
• Allelic analysis showed association of specific silent or intronic polymorphisms of the CHRNA3 and CHRNA4 genes and AD [23].
• Members of the ligand-gated neuronal nicotinic acetylcholine receptor (nAChR) gene family ( CHRNA4 and CHRNB2, coding for the alpha4 and beta2 subunits, respectively) are involved in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) [24].
• To identify the association between the CfoI polymorphism of the CHRNA4 and alcoholism, we examined distribution of genotypes and allele frequencies in Korean patients diagnosed with alcoholism (n = 127) and Korean control subjects without alcoholism (n = 185) with polymerase chain reaction-restriction fragment length polymorphism methods [16].
• A known Cfol polymorphism within the nicotinic acetylcholine alpha 4 receptor gene, CHRNA4, was studied in 70 ADHD parent-proband trios from an ongoing sample collection of children aged 6-12 with ADHD, according to DSM-IV criteria [25].

Analytical, diagnostic and therapeutic context of CHRNA4

• 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 [2].
• The new marker, which is detected by PCR, will be useful for evaluation of the role of CHRNA4 as a candidate gene for BFNC [26].
• A search for mutations of the genes coding for the most widely distributed nicotinic receptor subtype alpha4beta2 (CHRNA4/CHRNB2) has been performed in AD patients by screening the coding regions of both genes by single strand conformation analysis and heteroduplex analysis of fibroblast-derived genomic DNA [8].

References