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At last — linking ORMDL3 polymorphisms, decreased sphingolipid synthesis, and asthma susceptibility
Marsha Wills-Karp
Marsha Wills-Karp
Published January 13, 2020
Citation Information: J Clin Invest. 2020;130(2):604-607. https://doi.org/10.1172/JCI134333.
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Commentary

At last — linking ORMDL3 polymorphisms, decreased sphingolipid synthesis, and asthma susceptibility

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Abstract

Asthma is a common chronic respiratory disease that has a heritable component. Polymorphisms in the endoplasmic reticular protein orosomucoid-like protein 3 (ORMDL3), which regulates sphingolipid homeostasis, have been strongly linked with childhood-onset asthma. Despite extensive investigation, a link between ORMDL3 asthma–risk genotypes and altered sphingolipid synthesis has been lacking. In this issue of the JCI, Ono et al. establish a clear association between nonallergic childhood asthma, lower whole-blood sphingolipids, and asthma-risk 17q21 genotypes. These results demonstrate that genetic variants in ORMDL3 may confer a risk of developing childhood asthma through dysregulation of sphingolipid synthesis. As such, modulation of sphingolipids may represent a promising avenue of therapeutic development for childhood asthma.

Authors

Marsha Wills-Karp

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Figure 1

Potential role of genetic variants in ORMDL3 and childhood-onset asthma.

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Potential role of genetic variants in ORMDL3 and childhood-onset asthma....
The first and rate-limiting step in de novo SPH synthesis begins with the condensation of serine and palmitoyl-CoA by SPT to produce 3-ketosphingosine, which is rapidly converted to sphinganine. Sphinganine is then further metabolized by distinct ceramide synthases to dihydroceramides, which can then generate ceramides via dihydroceramide desaturases (DES1). Dihydroceramides can get phosphorylated to sphinganine-1-phosphate or get transported out of the ER to form complex sphingomyelins or glycosphingolipids. To maintain physiologic concentrations of SPHs in the ER, the lysosome can salvage and recycle complex SPHs (sphingomyelins, glycosphingolipids) from plasma membranes. As a consequence of increased ORMDL3 expression, de novo synthesis of SPHs is reduced. Reductions in whole-blood SPH levels have been associated with several features of childhood asthma including increased ASM contractility, airway remodeling, and airway hyperreactivity. GSL, glycosphingolipids; SM, sphingomyelins.
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