Characterization of the genomic structure of the human neuronal nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster and identification of novel intragenic polymorphisms

Abstract

Genes coding for the α5, α3, and 4 subunits (CHRNA5, CHRNA3, and CHRNB4) of the neuronal nicotinic acetylcholine receptors (nAChRs) are clustered on chromosome 15q24. Linkage of this chromosomal region to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), an idiopathic partial epilepsy, was reported in one family. Moreover, mutations in other neuronal nAChR subunit genes coding for the α4 (CHRNA4) and the 2 (CHRNB2) subunits were associated with ADNFLE. Apart from the exon-intron structure of CHRNA3, the genomic organization of this gene cluster was unknown, making comprehensive mutational analyses impossible. The genomic structure of CHRNA5 and CHRNB4 is here reported. Moreover, two hitherto unknown introns were identified within the 3Ј untranslated region of CHRNA3, causing a partial tail-to-tail overlap with CHRNA5. Four novel intragenic polymorphisms were identified and characterized in the cluster.

The CHRNA5/A3/B4 Gene Cluster Variability as an Important Determinant of Early Alcohol and Tobacco Initiation in Young Adults

“…The CHRNA5 and CHRNA3 genes partially overlap in a tail-to-tail configuration, sharing their 3′ ends. These two genes are transcribed in opposite directions and are clustered on chromosome 15q25.1 with the CHRNB4 gene (29,30). The structures of the CHRNA5/A3/B4 genes, and the SNPs selected, are shown in Figure 1.…”

Autonomic Nervous System Pharmacogenomics: A Progress Report

“…Numerous polymorphisms have been identified in ␣3, ␣4, ␣5, ␣7, ␤2, and ␤4 subunits (Table 2) (Steinlein et al, 1995;Weiland et al, 2000;Duga et al, 2001;Lev-Lehman et al, 2001;Leonard et al, 2002;Lueders et al, 2002). The nAChR genes for the ␤4, ␣3, and ␣5 subunits 1 Abbreviations: ANS, autonomic nervous system; BP, blood pressure; CNS, central nervous system; ACh, acetylcholine; NE, norepinephrine; nAChR, nicotinic ACh receptor; mAChR, muscarinic ACh receptor; AR, adrenergic receptors; SNP, single nucleotide polymorphism; GPCR, G protein-coupled receptor; AC, adenylyl cyclase; UTR, untranslated region; EPI, epinephrine; RFLP, restriction fragment length polymorphism; IDCM, idiopathic dilated cardiomyopathy; HASM, human airway smooth muscle; CGP12177, 4-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one.…”

“…The nAChR genes for the ␤4, ␣3, and ␣5 subunits 1 Abbreviations: ANS, autonomic nervous system; BP, blood pressure; CNS, central nervous system; ACh, acetylcholine; NE, norepinephrine; nAChR, nicotinic ACh receptor; mAChR, muscarinic ACh receptor; AR, adrenergic receptors; SNP, single nucleotide polymorphism; GPCR, G protein-coupled receptor; AC, adenylyl cyclase; UTR, untranslated region; EPI, epinephrine; RFLP, restriction fragment length polymorphism; IDCM, idiopathic dilated cardiomyopathy; HASM, human airway smooth muscle; CGP12177, 4-[3-[(1,1-dimethylethyl)amino]2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one. 32 KIRSTEIN AND INSEL are clustered on chromosome 15q24, and until recently, the gene structures (i.e., exact genomic size and exonintron boundaries) and the organization of the gene cluster were unknown, making comprehensive mutational analysis difficult (Weiland et al, 2000;Duga et al, 2001). The three genes in the cluster are physically linked (Raimondi et al, 1992), and the genes for the ␣3 and ␣5 subunits partially overlap at their 3Ј ends (Duga et al, 2001).…”

“…32 KIRSTEIN AND INSEL are clustered on chromosome 15q24, and until recently, the gene structures (i.e., exact genomic size and exonintron boundaries) and the organization of the gene cluster were unknown, making comprehensive mutational analysis difficult (Weiland et al, 2000;Duga et al, 2001). The three genes in the cluster are physically linked (Raimondi et al, 1992), and the genes for the ␣3 and ␣5 subunits partially overlap at their 3Ј ends (Duga et al, 2001). The genes in the cluster have been reported to be coexpressed, and regulatory elements that influence transcription of both the ␣3 and ␤4 genes have been identified (Deneris et al, 2000).…”

Nicotine addiction through a neurogenomic prism: Ethics, public health, and smoking

“…One branch of this research has explored polymorphisms (variants of genes) that may affect certain neurotransmitter pathways (specifically, dopamine, norepinephrine, GABA, and serotonin) that may play a role in predisposing an individual to nicotine addiction (Audrain et al, 1997;Bierut et al, 2000;Comings et al, 1996a;Dani & Heinemann, 1996;Heinz et al, 2000;Hu et al, 2000;Jorm et al, 2000;Koob, 1996;Lerman et al, 1998aLerman et al, , 1998bLerman et al, , 1999Lerman et al, , 2000Lerman et al, , 2001Lerman & Swan, 2002;Martinez et al, 2001;McKinney et al, 2000;Noble, 2000;Noble, Berman, Ozkaragoz, & Ritchie, 1994a;Noble et al, 1994c;Pidoplichko, DeBiasi, Williams, & Dani, 1997;Pontieri, Tanda, Orzi, & Di Chiara, 1996;Sabol et al, 1999;Shields et al, 1998;Spitz et al, 1998;Sullivan et al, 2001b;Vandenbergh et al, 2002). Another branch has examined genes that may influence an individual's response to nicotine (i.e., nicotine-specific pathways), including tolerance and sensitivity to nicotine Duga et al, 2001;Gault et al, 1998;London, Idle, Daly, & Coetzee, 1999;Oscarson et al, 1998;Perry, Davila-Garcia, Stockmeier, & Kellar, 1999;Pianezza, Sellers, & Tyndale, 1998;Sabol et al, 1999;Silverman et al, 2000;Slotkin, Pinkerton, Auman, Qiao, & Seidler, 2002). Finally, a third branch has studied genes in relation to treatment outcome …”