A MYLK variant regulates asthmatic inflammation via alterations in mRNA secondary structure
Article
Wang, T, Zhou, T, Saadat, L et al. (2015). A MYLK variant regulates asthmatic inflammation via alterations in mRNA secondary structure
. EUROPEAN JOURNAL OF HUMAN GENETICS, 23(6), 874-876. 10.1038/ejhg.2014.201
Wang, T, Zhou, T, Saadat, L et al. (2015). A MYLK variant regulates asthmatic inflammation via alterations in mRNA secondary structure
. EUROPEAN JOURNAL OF HUMAN GENETICS, 23(6), 874-876. 10.1038/ejhg.2014.201
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.
