ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins

Hjelmqvist, Lars; Tuson, Miquel; Marfany, Gemma; Herrero, Enric; Balcells, Susana; Gonzàlez‐Duarte, Roser

doi:10.1186/gb-2002-3-6-research0027

Cited by 153 publications

(56 citation statements)

References 39 publications

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“…The ORMDL family genes encode for transmembrane proteins located in the endoplasmic reticulum membrane. In mice, double knockout of the ORMDL genes leads to slower growth and higher sensitivity to toxic compounds in mice 42 . The function of the downstream ZPBP2 gene is not known.…”

Section: Discussionmentioning

confidence: 99%

Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants

Valk

Duijts

Timpson

et al. 2014

Journal of Allergy and Clinical Immunology

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Background The fractional concentration of nitric oxide in exhaled air (FeNO) is a biomarker of eosinophilic airway inflammation and associated with childhood asthma. Identification of common genetic variants associated with childhood FeNO may help to define biological mechanisms related to specific asthma phenotypes. Objective To identify genetic variants associated with childhood FeNO, and their relation with asthma. Methods FeNO was measured in children aged 5 to 15 years. In 14 genome-wide association (GWA) studies (N = 8,858), we examined the associations of ~2.5 million single nucleotide polymorphisms (SNPs) with FeNO. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci (eQTLs) in genome-wide expression datasets of lymphoblastoid cell lines (N = 1,830), and were related with asthma in a previously published GWA dataset (cases: n=10,365; controls: n=16,110). Results We identified 3 SNPs associated with FeNO: rs3751972 in LYR motif containing 9 (LYRM9) (P = 1.97×10−10) and rs944722 in inducible nitric oxide synthase 2 (NOS2) (P = 1.28×10−9) both located at 17q11.2-q12, and rs8069176 near gasdermin B (GSDMB) (P = 1.88×10−8) at 17q12-q21. We found a cis eQTL for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. Rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. Rs8069176 at 17q12-q21, and not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. Conclusion This study identified 3 variants associated with FeNO, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight in the regulation of FeNO. This study highlights that both shared and distinct genetic factors affect FeNO and childhood asthma.

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Section: Discussionmentioning

confidence: 99%

Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants

Valk

Duijts

Timpson

et al. 2014

Journal of Allergy and Clinical Immunology

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“…ORMDL3 (orosomucoid like 3), a gene located on chromosome 17q21 (1) has been strongly linked to asthma in genome wide association studies as well as in candidate gene association studies. ORMDL3 is a member of the ORDML gene family (ORMDL-1,-2,-3) which encode transmembrane proteins located at the endoplasmic reticulum (ER)(1).…”

Section: Introductionmentioning

confidence: 99%

“…ORMDL3 is a member of the ORDML gene family (ORMDL-1,-2,-3) which encode transmembrane proteins located at the endoplasmic reticulum (ER)(1). ORMDL-1 (chromosome 20)(1), and ORMDL-2 (chromosome 12)(1) are on different chromosomes from ORMDL-3 (chromosome 17q21)(1) and have not been linked to asthma. Both humans and mice express the same three ORMDL family members with ORMDL-3 exhibiting 96% identity between these two species (1).…”

Section: Introductionmentioning

confidence: 99%

“…ORMDL-1 (chromosome 20)(1), and ORMDL-2 (chromosome 12)(1) are on different chromosomes from ORMDL-3 (chromosome 17q21)(1) and have not been linked to asthma. Both humans and mice express the same three ORMDL family members with ORMDL-3 exhibiting 96% identity between these two species (1). ORMDL-3 is a 153 amino acid ER localized protein with two predicted transmembrane domains (1).…”

Section: Introductionmentioning

confidence: 99%

“…Both humans and mice express the same three ORMDL family members with ORMDL-3 exhibiting 96% identity between these two species (1). ORMDL-3 is a 153 amino acid ER localized protein with two predicted transmembrane domains (1). ORMDL3 regulates a number of pathways of potential importance to the pathogenesis of asthma including ATF6α, sphingolipids, remodeling genes, and chemokines (2, 3, 4).…”

Section: Introductionmentioning

confidence: 99%

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Cutting Edge: Targeting Epithelial ORMDL3 Increases, Rather than Reduces, Airway Responsiveness and Is Associated with Increased Sphingosine-1-Phosphate

Miller

Tam

Mueller

et al. 2017

The Journal of Immunology

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In this study we used cre-lox techniques to generate mice selectively deficient in ORMDL3 in airway epithelium (Ormdl3Δ2-3/Δ2-3CC10) to simulate an inhaled therapy that effectively inhibited ORMDL3 expression in the airway. In contrast to the anticipated reduction in airway responsiveness (AHR), OVA allergen challenged Ormdl3Δ2-3/Δ2-3CC10 mice had a significant increase in AHR compared to wild type (WT) mice. Levels of airway inflammation, mucus, fibrosis, and airway smooth muscle (ASM) were no different in Ormdl3Δ2-3/Δ2-3CC10 and WT mice. However, levels of sphingosine-1-phosphate (S1P) were significantly increased in Ormdl3Δ2-3/Δ2-3CC10 mice as well as in airway epithelial cells in which ORMDL3 was inhibited with siRNA. Incubation of S1P with ASM cells significantly increased contractility. Overall, Ormdl3Δ2-3/Δ2-3CC10 mice exhibit increased allergen induced AHR independent of inflammation and associated with increased S1P generation. These studies raise concerns for inhaled therapies that selectively and effectively inhibit ORMDL3 in airway epithelium in asthma.

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The sphingolipid anteome: implications for evolution of the sphingolipid metabolic pathway

2022

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Modern cell membranes contain a bewildering complexity of lipids, among them sphingolipids (SLs). Advances in mass spectrometry have led to the realization that the number and combinatorial complexity of lipids, including SLs, is much greater than previously appreciated. SLs are generated de novo by four enzymes, namely serine palmitoyltransferase, 3-ketodihydrosphingosine reductase, ceramide synthase and dihydroceramide D4-desaturase 1. Some of these enzymes depend on the availability of specific substrates and cofactors, which are themselves supplied by other complex metabolic pathways. The evolution of these four enzymes is poorly understood and likely depends on the co-evolution of the metabolic pathways that supply the other essential reaction components. Here, we introduce the concept of the 'anteome', from the Latin ante ('before') to describe the network of metabolic ('omic') pathways that must have converged in order for these pathways to co-evolve and permit SL synthesis. We also suggest that the current origin of life and evolutionary models lack appropriate experimental support to explain the appearance of this complex metabolic pathway and its anteome.

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ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins

Cited by 153 publications

References 39 publications

Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants

Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants

Cutting Edge: Targeting Epithelial ORMDL3 Increases, Rather than Reduces, Airway Responsiveness and Is Associated with Increased Sphingosine-1-Phosphate

The sphingolipid anteome: implications for evolution of the sphingolipid metabolic pathway

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