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Published ahead of print on September 25, 2003, doi:10.1165/rcmb.2003-0011OC

Am. J. Respir. Cell Mol. Biol., Volume 30, Number 5, May 2004, 678-686

A more recent version of this article appeared on May 1, 2004
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Submitted on January 15, 2003
Revised on September 25, 2003

Novel polymorphisms influencing transcription of the human CHRM2 gene in airway smooth muscle

Anthony G Fenech1, Charlotte K Billington2, Caroline Swan2, Susan Richards2, Therese Hunter3, Martin J Ebejer3, Alex E Felice3, Roger Ellul-Micallef1, and Ian P Hall2*

1 Clinical Pharmacology and Therapeutics, University of Malta, Msida, Malta, 2 Therapeutics, University of Nottingham, Nottingham, Notts, United Kingdom, 3 Physiology and Biochemistry, University of Malta, Msida, Malta

* To whom correspondence should be addressed. E-mail: ian.hall{at}nottingham.ac.uk.

Muscarinic receptors are a functionally important family of G-protein coupled receptors. Using a combination of 5'RACE and reporter gene assays, we characterised the 5'UTR of the CHRM2 gene as expressed in human airway smooth muscle (HASM) cells. A splice site is present 46bp upstream from the ATG start codon. Five exons with alternative splicing patterns are present upstream of this splice site, separated by introns ranging from 87bp to >145kb. There is evidence for the gene being under the control of a TATA-less promoter with Sp1, GATA and AP-2 binding sites. Multiple transcription start sites (TSSs) were identified. We identified a novel 0.5kb hypervariable region located 648bp upstream of the most 5' TSS, a multiallelic (CA) tandem repeat 96bp downstream of the most 5' TSS and a common C{Rightarrow}A SNP located 136bp upstream of the most 5' TSS. Functional studies in primary HASM cells and the BEAS-2B cell line, demonstrated highest promoter activity to be upstream of the most 3' TSS, with potential repressor elements operating in a cell-type dependent manner, located upstream of the most 5' TSS. We present functional data to show that the CA repeat may influence the transcription of the gene in HASM and BEAS-2B cells.




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