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General Information
Name
asthma, susceptibility to, ORMDL3-related
FlyBase ID
FBhh0001038
Disease Ontology Term
Parent Disease
OMIM
Overview

This report describes asthma, susceptibility to, ORMDL3-related.

The human gene implicated in this disease is ORMDL-3 (orosomucoid 1-like 3, ORMDL sphingolipid biosynthesis regulator 3). There is one high-ranking ortholog of ORMDL-3 in Drosophila, ORMDL. Multiple alleles have been generated for ORMDL, including an overexpression construct, multiple RNAi targeting constructs, and insertion lines.

The human gene ORMDL3 has not been introduced into flies. The closely related human paralog Hsap\ORMDL1 has been introduced into flies, Hsap\ORMDL1UAS.Tag:HA, but it has not yet been characterized.

Overexpression of Dmel\ORMDL in Drosophila airway epithelia causes a reduction in the number and size of branches of termina tracheal cells (FBbt:00005053), equivalent to alveoli. Mutant larvae responded faster to avoid a hypoxic environment (5% oxygen), and ORMDL-expressing adults exposed to cigarette smoke had a reduced lifespan, compared to matched controls. ORMDL-overexpressing flies also had reduced expression of EGFR signaling target genes (ac, spi, cora), consistent with the hypothesis that defective epithelial repair caused by EGFR signaling is linked to asthma development.

[updated May 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: asthma, susceptibility to, ORMDL3-related
OMIM report

[ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO, 6](https://omim.org/entry/611403)

Human gene(s) implicated

[ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO, 6](https://omim.org/entry/611403)

Symptoms and phenotype

Asthma-related traits include clinical symptoms of asthma, such as coughing, wheezing, and dyspnea; bronchial hyperresponsiveness (BHR) as assessed by methacholine challenge test; serum IgE levels; atopy; and atopic dermatitis (Laitinen et al. 2001, pubmed:11326283; Illig and Wjst, 2002, pubmed:12065182; Pillai et al. 2006, pubmed:16391567). [from OMIM 611403, 2019.05.17]

Genetics

Elucidation of ORMDL3's functional relevance in asthma pathogenesis has been hindered by extensive similarities between all 3 ORMDL proteins (ORMDL1-3) as well as their strongly overlapping expression patterns. (Kallsen et al. 2015, FBrf0229810)

Although asthma-associated polymorphisms in 17q21 were first linked to orosomucoid 1-like 3 (ORMDL3) gene expression,1 allele-specific effects of these polymorphisms on the expression of other genes in the region were subsequently also shown in adults (GSDMB,1ORMDL3, and ZPBP22) and cord blood (ORMDL3 and GSDMA). Although other genes within 17q21 might contribute to the asthma association signal, ORMDL3 remains a major asthma candidate gene in this locus. (Schedel et al. 2015, pubmed:25930191)

The SNPs associated with childhood asthma were consistently and strongly associated (p less than 10(-22)) in cis with transcript levels of ORMDL3 (610075), a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum. Moffatt et al. 2007 (pubmed:17611496) concluded that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma. In the subset of individuals for whom expression data were available, the T nucleotide allele of SNP rs7216389, the marker most strongly associated with disease in the combined genomewide analysis, had a frequency of 62% among asthmatics compared to 52% in nonasthmatics (p = 0.005 in this sample). The additive effect of this allele corresponds to a change of 0.78 standard deviation units in ORMDL3 expression (p less than 10(-22)).

[from OMIM 611403, 2019.05.17]

Cellular phenotype and pathology

Work in human epithelial cells and mice supports the involvment of ORMDL3 in allergic inflammation. (Schedel et al. 2015, pubmed:25930191)

Molecular information

ORMDL3 is 1 of 3 members of the ORMDL family in mammals; it encodes an endoplasmic reticulum transmembrane protein that is implicated in diverse cellular processes. (Kallsen et al. 2015, FBrf0229810)

External links
Disease synonyms
ASRT6
Asthma-related traits, susceptibility to, 6
Ortholog Information
Human gene(s) in FlyBase
    Human gene (HGNC)
    D. melanogaster ortholog (based on DIOPT)
    Comments on ortholog(s)

    Many human genes to one Drosophila gene.

    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (1)
      Gene Snapshot
      In progress.Contributions welcome.
      Molecular function (GO)
        Gene Groups / Pathways
          Comments on ortholog(s)

          High-to-moderate-ranking ortholog of ORMDL1, ORMDL2, and ORMDL3.

          Orthologs and Alignments from DRSC
          DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
          Synthetic Gene(s) Used (0)
          Summary of Physical Interactions (0 groups)
          Alleles Reported to Model Human Disease (Disease Ontology) (1 alleles)
          Models Based on Experimental Evidence ( 1 )
          Allele
          Disease
          Evidence
          References
          Modifiers Based on Experimental Evidence ( 0 )
          Allele
          Disease
          Interaction
          References
          Genetic Tools, Stocks and Reagents
          Sources of Stocks
          Contact lab of origin for a reagent not available from a public stock center.
          Bloomington Stock Center Disease Page
          Selected mammalian transgenes
          Allele
          Transgene
          Publicly Available Stocks
          Selected Drosophila transgenes
          Allele
          Transgene
          Publicly Available Stocks
          RNAi constructs available
          Allele
          Transgene
          Publicly Available Stocks
          Selected Drosophila classical alleles
          Allele
          Allele class
          Mutagen
          Publicly Available Stocks
          References (7)