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Chromosome 17q21 Genes ORMDL3 and GSDMB in Asthma and Immune Diseases.
- Source :
-
Advances in immunology [Adv Immunol] 2017; Vol. 135, pp. 1-52. Date of Electronic Publication: 2017 Jul 19. - Publication Year :
- 2017
-
Abstract
- Chromosome 17q21 contains a cluster of genes including ORMDL3 and GSDMB, which have been highly linked to asthma in genome-wide association studies. ORMDL3 is localized to the endoplasmic reticulum and regulates downstream pathways including sphingolipids, metalloproteases, remodeling genes, and chemokines. ORMDL3 inhibits serine palmitoyl-CoA transferase, the rate-limiting enzyme for sphingolipid biosynthesis. In addition, ORMDL3 activates the ATF6α branch of the unfolded protein response which regulates SERCA2b and IL-6, pathways of potential importance to asthma. The SNP-linking chromosome 17q21 to asthma is associated with increased ORMDL3 and GSDMB expression. Mice expressing either increased levels of human ORMDL3, or human GSDMB, have an asthma phenotype characterized by increased airway responsiveness and increased airway remodeling (increased smooth muscle and fibrosis) in the absence of airway inflammation. GSDMB regulates expression of 5-LO and TGF-β1 which are known pathways involved in the pathogenesis of asthma. GSDMB is one of four members of the GSDM family (GSDMA, GSDMB, GSDMC, and GSDMD). GSDMD (located on chromosome 8q24 and not linked to asthma) has emerged as a key mediator of pyroptosis. GSDMD is a key component of the NLPR3 inflammasome and is required for its activation. GSDMD undergoes proteolytic cleavage by caspase-1 to release its N-terminal fragment, which in turn mediates pyroptosis and IL-1β secretion. Chromosome 17q21 has not only been linked to asthma but also to type 1 diabetes, inflammatory bowel disease, and primary biliary cirrhosis suggesting that future insights into the biology of genes located in this region will increase our understanding of these diseases.<br /> (© 2017 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Asthma genetics
Asthma pathology
Chemokines genetics
Chemokines immunology
Chromosomes, Human, Pair 17 chemistry
Chromosomes, Human, Pair 17 immunology
Diabetes Mellitus, Type 1 genetics
Diabetes Mellitus, Type 1 pathology
Gene Expression Regulation
Humans
Inflammatory Bowel Diseases genetics
Inflammatory Bowel Diseases pathology
Liver Cirrhosis, Biliary genetics
Liver Cirrhosis, Biliary pathology
Membrane Proteins genetics
Mice
Multigene Family
Neoplasm Proteins genetics
Polymorphism, Genetic
Protein Isoforms genetics
Protein Isoforms immunology
Signal Transduction
Sphingolipids immunology
Sphingolipids metabolism
Asthma immunology
Diabetes Mellitus, Type 1 immunology
Inflammatory Bowel Diseases immunology
Liver Cirrhosis, Biliary immunology
Membrane Proteins immunology
Neoplasm Proteins immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1557-8445
- Volume :
- 135
- Database :
- MEDLINE
- Journal :
- Advances in immunology
- Publication Type :
- Academic Journal
- Accession number :
- 28826527
- Full Text :
- https://doi.org/10.1016/bs.ai.2017.06.001