Ormdl sphingolipid biosynthesis regulator 3

ORMDL sphingolipid biosynthesis regulator 3 is a protein that in humans is encoded by the ORMDL3 gene. Variants affecting the expression of this gene are associated with asthma in childhood. Transgenic mice which overexpress human ORMDL3 have increased levels of IgE. This correlated with increased numbers of macrophages, neutrophils, eosinophils, CD4⁺ and enhanced Th2 cytokine levels in the lung tissue.

Localisation

The ORMDL family, whose name stands for ORM1 (Saccharomyces cerevisiae)–like genes, consists of three members (ORMDL1-3) which are localised in the membrane of the endoplasmic reticulum (ER). All three human ORMDL genes encode 153 amino acid products. The genes ORMDL1, ORMDL2 and ORMDL3 are located on human chromosomes 2q32, 12q13.2 and 17q21, respectively.

Function

ORMDL3 negatively regulates de novo sphingolipid synthesis through interaction with serine palmitoyltransferase (SPT), but it may be present in relative excess of SPT physiologically, as ORMDL3 overexpression does not significantly reduce cellular sphingolipid biosynthesis. ORMDL3 also has a role in regulating Ca²⁺ levels in the endoplasmic reticulum. The ER is very important for generation, signaling function and storage of intracellular Ca²⁺. There are channels, which control the exit of Ca²⁺ from the ER into the cytoplasm and also pumps (sarco-endoplasmic reticulum Ca²⁺ ATPase or SERCA) which return Ca²⁺ back to the ER. Dysregulation of Ca²⁺ has the key role in several pathological conditions like dysfunction of SERCA, asthma, and Alzheimer's.

Clinical significance

Mutations in ORMDL3 are associated with inflammatory diseases like Crohn's disease, type 1 diabetes, and rheumatoid arthritis.