Abstract
Single nucleotide polymorphisms (SNPs) located within the human chromosomal region 17q21 are strongly associated with the incidence of inherited (early onset or childhood) asthma. These SNPs lead to increased transcription of nearby genes, including ORMDL3. Studies in Saccharomyces cerevisiae have identified the yeast Ormdl3 orthologs, Orm1 and Orm2, as components of and negative regulators of the enzyme complex, serine:palmitoyl‐CoA transferase (SPT), which catalyzes the first step in sphingolipid biosynthesis. Ormdl3 and its paralogs Ormdl1 and Ormdl2 have been likewise suggested to associate with and negatively regulate mammalian SPT. Here, we show that overexpression of Ormdl3 can rescue the phytosphingosine sensitivity of an orm1 orm2 double delete strain of yeast. Moreover, Ormdl3 overexpression in HEK cells either transiently or using an inducible Tet‐on system also results in a marked inhibition in SPT activity. Given its inhibitory function, higher Ormdl3 level (in the asthma patients carrying the SNPs) should diminish sphingolipid biosynthesis, perhaps causing an imbalance in the sphingolipid to glycerolipid composition of the plasma membrane. To confirm this initial observation we have raised polyclonal antisera against Ormdl3 and are currently investigating the fold increase in Ormdl3 protein in the bronchi and lungs of asthma patients carrying these SNPs.
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