A MYLK variant regulates asthmatic inflammation via alterations in mRNA secondary structure.

TitleA MYLK variant regulates asthmatic inflammation via alterations in mRNA secondary structure.
Publication TypeJournal Article
Year of Publication2015
AuthorsWang T, Zhou T, Saadat L, Garcia JGN
JournalEur J Hum Genet
Date Published2015 Jun
ISSN Number1476-5438
KeywordsAnimals, Asthma, Calcium-Binding Proteins, Cell Line, Humans, Inflammation, Mice, Myosin-Light-Chain Kinase, Nucleic Acid Conformation, Peptide Chain Initiation, Translational, Polymorphism, Single Nucleotide, RNA Stability, RNA, Messenger

<p>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.</p>

Alternate JournalEur. J. Hum. Genet.
PubMed ID25271083
PubMed Central IDPMC4795064
Grant ListP01 HL058064 / HL / NHLBI NIH HHS / United States
R01 HL091889 / HL / NHLBI NIH HHS / United States
HL 58064 / HL / NHLBI NIH HHS / United States
HL 91899 / HL / NHLBI NIH HHS / United States