title: A MYLK variant regulates asthmatic inflammation via alterations in mRNA secondary structure.
abstract: Myosin light-chain kinase (MYLK) is a gene known to be significantly associated with severe asthma in African Americans. Here we further examine the molecular function of a single-nucleotide polymorphism (SNP), located in the non-muscle myosin light-chain kinase isoform (nmMLCK), in asthma susceptibility and pathobiology. We identified nmMLCK variant (reference SNP: rs9840993, NM_053025: 721C>T, c.439C>T) with a distinct mRNA secondary structure from the other variants. The nmMLCK variant (721C) secondary structure exhibits increased stability with an elongated half-life in the human endothelial cell, and greater efficiency in protein translation initiation owing to an increased accessibility to translation start site. Finally, nmMLCK expression of 721C- and 721T-containing MYLK transgenes were compared in nmMLCK(-/-) mice and confirmed deleterious effects of nmMLCK expression on asthmatic indices and implicated the augmented influence of MYLK 721C>T (c.439C>T) SNP on asthma severity. The confirmation of the novel mechanism of the regulation of asthmatic inflammation by a MYLK advances knowledge of the genetic basis for asthma disparities, and further suggests the potential of nmMLCK as a therapeutic target. Our study suggests that in addition to altering protein structure and function, non-synonymous SNPs may also lead to phenotypic disparity by altering protein expression.
authors.affiliation: Arizona Respiratory Center and Department of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Arizona Respiratory Center and Department of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Arizona Respiratory Center and Department of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Laleh
authors.initials: L
authors.lastname: Saadat
authors.affiliation: Arizona Respiratory Center and Department of Medicine, University of Arizona, Tucson, AZ, USA.
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000235:genetics; D051379:Mice; D009219:Myosin-Light-Chain Kinase / Q000235:genetics* / Q000378:metabolism; D009690:Nucleic Acid Conformation; D010442:Peptide Chain Initiation, Translational; D020641:Polymorphism, Single Nucleotide; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry* / Q000235:genetics
chemical_list: D002135:Calcium-Binding Proteins; D012333:RNA, Messenger; C499378:MYLK protein, human; D009219:Myosin-Light-Chain Kinase