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- Title
A MYLK variant regulates asthmatic inflammation via alterations in mRNA secondary structure.
- Authors
Wang, Ting; Zhou, Tong; Saadat, Laleh; Garcia, Joe GN
- 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.
- Subjects
MYOSIN light chain kinase; ASTHMA diagnosis; SINGLE nucleotide polymorphisms; HEALTH of African Americans; MYOSIN genetics
- Publication
European Journal of Human Genetics, 2015, Vol 23, Issue 6, p874
- ISSN
1018-4813
- Publication type
Article
- DOI
10.1038/ejhg.2014.201