A MYLK variant regulates asthmatic inflammation via alterations in mRNA secondary structure.
Eur J Hum Genet
; 23(6): 874-6, 2015 Jun.
Article
in En
| MEDLINE
| ID: mdl-25271083
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Asthma
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Myosin-Light-Chain Kinase
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Calcium-Binding Proteins
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RNA, Messenger
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Polymorphism, Single Nucleotide
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Nucleic Acid Conformation
Limits:
Animals
/
Humans
Language:
En
Journal:
Eur J Hum Genet
Year:
2015
Document type:
Article