The Gene Is Involved in Hirschsprung Associated Enterocolitis Susceptibility Through an Altered Downstream Signaling

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Apr 30

PMID 33917126

Citations 5

Authors

Tiziana Bachetti

Francesca Rosamilia

Martina Bartolucci

Giuseppe Santamaria

Manuela Mosconi

Serenella Sartori

Maria Rosaria De Filippo

Marco Di Duca

Valentina Obino

Stefano Avanzini

Domenico Mavilio

Simona Candiani

Andrea Petretto

Alessio Pini Prato

Isabella Ceccherini

Francesca Lantieri

Affiliations

Soon will be listed here.

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 () gene (14.6% in HAEC and 5.1% in HSCR-only, = 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 ( < 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, p.H187Q is an HAEC susceptibility variant and perturbates the downstream signaling cascade necessary for the gut immune response and homeostasis maintenance.

Citing Articles

16S rRNA Sequencing Reveals Alterations of Gut Bacteria in Hirschsprung-Associated Enterocolitis.

Shi H, She Y, Mao W, Xiang Y, Xu L, Yin S Glob Med Genet. 2024; 11(4):263-269.

PMID: 39176109 PMC: 11341197. DOI: 10.1055/s-0044-1789237.

Update on the Pathogenesis of the Hirschsprung-Associated Enterocolitis.

Li S, Zhang Y, Li K, Liu Y, Chi S, Wang Y Int J Mol Sci. 2023; 24(5).

PMID: 36902033 PMC: 10003052. DOI: 10.3390/ijms24054602.

Microcytic hypochromic Anemia is a risk factor for postoperative HAEC: A retrospective study.

Huang Y, Ren H Front Surg. 2023; 10:1055128.

PMID: 36874458 PMC: 9975337. DOI: 10.3389/fsurg.2023.1055128.

OSM/OSMR and Interleukin 6 Family Cytokines in Physiological and Pathological Condition.

Lantieri F, Bachetti T Int J Mol Sci. 2022; 23(19).

PMID: 36232392 PMC: 9569747. DOI: 10.3390/ijms231911096.

Different Fecal Microbiota in Hirschsprung's Patients With and Without Associated Enterocolitis.

Arnaud A, Cousin I, Schmitt F, Petit T, Parmentier B, Levard G Front Microbiol. 2022; 13:904758.

PMID: 35847080 PMC: 9279138. DOI: 10.3389/fmicb.2022.904758.

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