Research ArticleAsthma

Impaired Sphingolipid Synthesis in the Respiratory Tract Induces Airway Hyperreactivity

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Science Translational Medicine  22 May 2013:
Vol. 5, Issue 186, pp. 186ra67
DOI: 10.1126/scitranslmed.3005765

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Breathing Easy

The explosion in genome-wide association studies (GWAS) has implicated countless genes in the pathology of diverse diseases. Yet, when it comes to developing new therapies, associations aren’t enough. Studies must functionally connect GWAS-implicated targets to disease pathology. Now, Worgall et al. demonstrate that orosomucoid-like 3 (ORMDL3) and downstream sphingolipids may play a pathogenic role in asthma.

ORM proteins negatively regulate sphingolipid synthesis through their effects on serine palmitoyl-CoA transferase (SPT), which is required for sphingolipid generation. ORMDL3 has been associated with asthma in several GWAS; the authors therefore hypothesized that SPT and sphingolipids may contribute to asthma pathogenesis. They found that either decreasing sphingolipid synthesis or inhibiting SPT with myriocin increased bronchioreactivity in the absence of inflammation in part by altered bronchial sensitivity to magnesium. These data functionally link sphingolipid synthesis and airway hyperactivity, and suggest that this pathway may be a new target for asthma therapy.