title: Multiple isoforms and differential allelic expression of CHRNA5 in lung tissue and lung adenocarcinoma.
abstract: CHRNA5 gene expression variation may play a role in individual susceptibility to lung cancer. Analysis of CHRNA5 transcripts expressed in normal lung tissue detected the full-length transcript (isoform-1) and four splicing transcripts (isoform-2 to isoform-5), derived from the recognition of other splice sites in exon 5. Isoforms-2, -3 and -4 were found by protein modeling to form a completely folded, potentially functional extracellular domain and were observed at the protein level, whereas isoform-5 lacked a consistent part of the distorted β sandwich and was not seen at the protein level. Only isoform-1 appeared to encode a complete, functional subunit able to fulfill the ion channel function. We previously reported that CHRNA5 expression is associated with genetic polymorphisms at this locus and that three haplotypes in its promoter region show functional regulation in vitro. Analysis of differential allelic expression (DAE) of three single nucleotide polymorphisms (rs503464, rs55853698 and rs55781567) tagging the expression haplotypes of the CHRNA5 promoter indicated statistically significant DAE at rs55853698 and rs55781567, in both normal lung and lung adenocarcinoma. Overall, our findings provide evidence for the presence of multiple CHRNA5 messenger RNA (mRNA) isoforms that may modulate the multimeric nicotine receptor and cis-regulatory variations in the CHRNA5 locus that act in vivo in the control of CHRNA5 mRNA expression, in normal lung tissue and in lung adenocarcinoma.
authors: Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy.
authors: Felicia S
authors: FS
authors: Falvella
authors: Tiziana
authors: T
authors: Alberio
authors: Sara
authors: S
authors: Noci
authors: Luigi
authors: L
authors: Santambrogio
authors: Mario
authors: M
authors: Nosotti
authors: Matteo
authors: M
authors: Incarbone
authors: Ugo
authors: U
authors: Pastorino
authors: Mauro
authors: M
authors: Fasano
authors: Tommaso A
authors: TA
authors: Dragani
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D015810:Linkage Disequilibrium; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: C447158:CHRNA5 protein, human; D007473:Ion Channels; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D011978:Receptors, Nicotinic