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.
Highlights
Within a rising US and world-wide prevalence of asthma, there is strong evidence for ethnic disparities in asthma susceptibility and severity with greater mortality,[1] more severe obstruction and greater number of severe attacks occurring in asthmatics of African descent (AD).[2]
We recently explored Myosin light-chain kinase (MYLK), a gene encoding the Ca2+/calmodulin-dependent myosin light-chain kinase (MLCK), as a candidate gene for asthma susceptibility[3] taking advantage of extensive gene resequencing in samples from Europeans and African Americans.[4]
We identified the significant association of an African-specific nonsynonymous variant in MYLK (reference single-nucleotide polymorphism (SNP): rs9840993, NM_053025: 721C4T, p.Pro147Ser or c.439C4T) with severe asthma.[3]
Summary
Within a rising US and world-wide prevalence of asthma, there is strong evidence for ethnic disparities in asthma susceptibility and severity with greater mortality,[1] more severe obstruction and greater number of severe attacks occurring in asthmatics of African descent (AD).[2].
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