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The OSMR Gene Is Involved in Hirschsprung Associated Enterocolitis Susceptibility through an Altered Downstream Signaling
- Source :
- International Journal of Molecular Sciences, International Journal of Molecular Sciences, Vol 22, Iss 3831, p 3831 (2021), Web of Science, Volume 22, Issue 8
- Publication Year :
- 2021
- Publisher :
- MDPI, 2021.
-
Abstract
- Hirschsprung (HSCR) Associated Enterocolitis (HAEC) is a common life-threatening complication in HSCR. HAEC is suggested to be due to a loss of gut homeostasis caused by impairment of immune system, barrier defense, and microbiome, likely related to genetic causes. No gene has been claimed to contribute to HAEC occurrence, yet. Genetic investigation of HAEC by Whole-Exome Sequencing (WES) on 24 HSCR patients affected (HAEC) or not affected (HSCR-only) by enterocolitis and replication of results on a larger panel of patients allowed the identification of the HAEC susceptibility variant p.H187Q in the Oncostatin-M receptor (OSMR) gene (14.6% in HAEC and 5.1% in HSCR-only, p = 0.0024). Proteomic analysis on the lymphoblastoid cell lines from one HAEC patient homozygote for this variant and one HAEC patient not carrying the variant revealed two well distinct clusters of proteins significantly up or downregulated upon OSM stimulation. A marked enrichment in immune response pathways (q &lt<br />0.0001) was shown in the HAEC H187 cell line, while proteins upregulated in the HAEC Q187 lymphoblasts sustained pathways likely involved in pathogen infection and inflammation. In conclusion, OSMR p.H187Q is an HAEC susceptibility variant and perturbates the downstream signaling cascade necessary for the gut immune response and homeostasis maintenance.
- Subjects :
- Models, Molecular
Protein Conformation
Gene Expression
Oncostatin-M receptor (OSMR)
lcsh:Chemistry
Gene Frequency
Receptor
lcsh:QH301-705.5
Spectroscopy
Enterocolitis
Oncostatin M Receptor beta Subunit
General Medicine
Computer Science Applications
cardiovascular system
Gut inflammation
Hirschsprung Associated Enterocolitis (HAEC)
Mucosal immunity
Proteomics
Whole-Exome Sequencing (WES)
Disease Susceptibility
gut inflammation
medicine.symptom
Signal Transduction
Genotype
Inflammation
Biology
Catalysis
Article
Inorganic Chemistry
Structure-Activity Relationship
Immune system
proteomics
Downregulation and upregulation
Exome Sequencing
medicine
Humans
Hirschsprung Disease
Microbiome
Physical and Theoretical Chemistry
Molecular Biology
Gene
Alleles
Whole Genome Sequencing
Organic Chemistry
Genetic Variation
lcsh:Biology (General)
lcsh:QD1-999
Cell culture
Cancer research
mucosal immunity
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Volume :
- 22
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences
- Accession number :
- edsair.doi.dedup.....f66b0a5f3f9f4a603cc53b576ce45f89