A novel biallelic 19-bp deletion in the IL10RB gene caused infant-onset inflammatory bowel disease in a consanguineous family: a molecular docking simulation study and literature review.
IL10RB gene
Inflammatory bowel diseases
Iran
Mutation
Whole exome sequencing
Journal
Molecular biology reports
ISSN: 1573-4978
Titre abrégé: Mol Biol Rep
Pays: Netherlands
ID NLM: 0403234
Informations de publication
Date de publication:
28 Jan 2024
28 Jan 2024
Historique:
received:
26
11
2023
accepted:
11
01
2024
medline:
28
1
2024
pubmed:
28
1
2024
entrez:
28
1
2024
Statut:
epublish
Résumé
Infantile-onset inflammatory bowel disease (IOIBD) is a gastrointestinal inflammatory condition often associated with monogenic disorders and is frequently caused by Interleukin-10 deficiencies. This study aimed to identify the mutation responsible for IBD in an 8-year-old patient from an Iranian family with consanguineous parents. Whole-exome sequencing (WES) was employed to identify disease-causing variations. Furthermore, we utilized integrated experimental data of HADDOCK molecular docking platform, including NMR spectroscopy, to characterize the mutant protein and elucidate the underlying functional mechanism of the identified mutation's pathogenicity. Our findings revealed a novel 19-bp deletion mutation (c.25_43del, p.Leu9CysfsTer15) in the IL10RB gene. Sanger sequencing confirmed that this variant was inherited in homozygous state within this family, marking the first mutation identified in exon 1 of this gene. Molecular docking simulation demonstrated that the mutant form of IL10RB exhibited reduced affinity for binding to the Interleukin-10 ligand, leading to disruptions in downstream cellular signaling pathways. The identification of this novel genetic variant as a causative factor for IOIBD highlights the clinical value of utilizing genetic testing, such as WES, as a reliable diagnostic approach for patients affected by this condition.
Sections du résumé
BACKGROUND
BACKGROUND
Infantile-onset inflammatory bowel disease (IOIBD) is a gastrointestinal inflammatory condition often associated with monogenic disorders and is frequently caused by Interleukin-10 deficiencies. This study aimed to identify the mutation responsible for IBD in an 8-year-old patient from an Iranian family with consanguineous parents.
METHODS
METHODS
Whole-exome sequencing (WES) was employed to identify disease-causing variations. Furthermore, we utilized integrated experimental data of HADDOCK molecular docking platform, including NMR spectroscopy, to characterize the mutant protein and elucidate the underlying functional mechanism of the identified mutation's pathogenicity.
RESULTS
RESULTS
Our findings revealed a novel 19-bp deletion mutation (c.25_43del, p.Leu9CysfsTer15) in the IL10RB gene. Sanger sequencing confirmed that this variant was inherited in homozygous state within this family, marking the first mutation identified in exon 1 of this gene. Molecular docking simulation demonstrated that the mutant form of IL10RB exhibited reduced affinity for binding to the Interleukin-10 ligand, leading to disruptions in downstream cellular signaling pathways.
CONCLUSIONS
CONCLUSIONS
The identification of this novel genetic variant as a causative factor for IOIBD highlights the clinical value of utilizing genetic testing, such as WES, as a reliable diagnostic approach for patients affected by this condition.
Identifiants
pubmed: 38281300
doi: 10.1007/s11033-024-09248-4
pii: 10.1007/s11033-024-09248-4
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
223Subventions
Organisme : Golestan University of Medical Sciences
ID : 113339
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature B.V.
Références
Ramos GP, Papadakis KA (2019) Mechanisms of disease: inflammatory bowel diseases. in Mayo Clinic Proceedings. Elsevier
Noor NM et al (2020) Personalised medicine in Crohn’s disease. Lancet Gastroenterol Hepatol 5(1):80–92
doi: 10.1016/S2468-1253(19)30340-1
pubmed: 31818474
Nemeth ZH et al (2017) Crohn’s disease and ulcerative colitis show unique cytokine profiles. Cureus, 9(4)
Le Berre C et al (2020) Ulcerative colitis and Crohn’s disease have similar burden and goals for treatment. Clin Gastroenterol Hepatol 18(1):14–23
doi: 10.1016/j.cgh.2019.07.005
pubmed: 31301452
Ganesh R et al (2022) Clinical spectrum of monogenic infantile-onset inflammatory bowel disease. Indian J Pediatr 89(5):497–502
doi: 10.1007/s12098-022-04103-5
pubmed: 35246832
Shah N et al (2012) Interleukin-10 and interleukin-10–receptor defects in inflammatory bowel disease. Curr Allergy Asthma Rep 12:373–379
doi: 10.1007/s11882-012-0286-z
pubmed: 22890722
Graham DB, Xavier RJ (2020) Pathway paradigms revealed from the genetics of inflammatory bowel disease. Nature 578(7796):527–539
doi: 10.1038/s41586-020-2025-2
pubmed: 32103191
pmcid: 7871366
The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017 Lancet Gastroenterol Hepatol, (2020) 5(1): p. 17–30
Loddo I, Romano C (2015) Inflammatory bowel disease: Genetics, Epigenetics, and Pathogenesis. Front Immunol 6:551
doi: 10.3389/fimmu.2015.00551
pubmed: 26579126
pmcid: 4629465
Uhlig HH et al (2014) The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 147(5):990–1007e3
doi: 10.1053/j.gastro.2014.07.023
pubmed: 25058236
Dorgaleleh S et al (2022) Whole exome sequencing reveals the first c. 7456C > T p. Arg2486X mutation in ATM gene in Iranian population. Health Biotechnol Biopharma (HBB) 6(3):57–72
Fattahi Z et al (2019) Iranome: a catalog of genomic variations in the Iranian population. Hum Mutat 40(11):1968–1984
doi: 10.1002/humu.23880
pubmed: 31343797
Naghipoor K, Khosravi T, Oladnabi M (2023) Whole exome sequencing identifies a novel variant in the COL12A1 gene in a family with Ullrich congenital muscular dystrophy 2. Mol Biol Rep 50(9):7427–7435
doi: 10.1007/s11033-023-08644-6
pubmed: 37458870
Hajilari M et al (2023) Frequency of c.35delG Mutation in GJB2 gene in patients with autosomal recessive non-syndromic hearing loss of five ethnic groups in Golestan, Iran. Int J Pediatr 11(1):17286–17298
Acuner-Ozbabacan ES et al (2014) The structural network of Interleukin-10 and its implications in inflammation and cancer. BMC Genomics 15(Suppl 4):S2
doi: 10.1186/1471-2164-15-S4-S2
pubmed: 25056661
pmcid: 4083408
Mering Cv et al (2003) STRING: a database of predicted functional associations between proteins. Nucleic Acids Res 31(1):258–261
doi: 10.1093/nar/gkg034
Kammermeier J et al (2017) Phenotypic and genotypic characterisation of inflammatory bowel Disease presenting before the age of 2 years. J Crohns Colitis 11(1):60–69
doi: 10.1093/ecco-jcc/jjw118
pubmed: 27302973
Uhlig HH (2013) Monogenic diseases associated with intestinal inflammation: implications for the understanding of inflammatory bowel disease. Gut 62(12):1795–1805
doi: 10.1136/gutjnl-2012-303956
pubmed: 24203055
Anjani G et al (2020) Recent advances in chronic granulomatous disease. Genes Dis 7(1):84–92
doi: 10.1016/j.gendis.2019.07.010
pubmed: 32181279
Worthey EA et al (2011) Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med 13(3):255–262
doi: 10.1097/GIM.0b013e3182088158
pubmed: 21173700
Speckmann C, Ehl S (2014) XIAP deficiency is a mendelian cause of late-onset IBD. Gut 63(6):1031–1032
doi: 10.1136/gutjnl-2013-306474
pubmed: 24326742
Kotlarz D et al (2012) Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology 143(2):347–355
doi: 10.1053/j.gastro.2012.04.045
pubmed: 22549091
Verma R et al (2016) A network map of Interleukin-10 signaling pathway. J Cell Commun Signal 10(1):61–67
doi: 10.1007/s12079-015-0302-x
pubmed: 26253919
Shi J et al (2016) IL10 inhibits starvation-induced autophagy in hypertrophic scar fibroblasts via cross talk between the IL10-IL10R-STAT3 and IL10-AKT-mTOR pathways. Cell Death Dis 7(3):e2133
doi: 10.1038/cddis.2016.44
pubmed: 26962683
pmcid: 4823945
Zhu L et al (2017) IL-10 and IL-10 receptor mutations in very early onset inflammatory bowel disease. Gastroenterol Res 10(2):65
doi: 10.14740/gr740w
Ramírez-Pérez S et al (2020) Downregulation of inflammatory cytokine release from IL-1β and LPS-stimulated PBMC orchestrated by ST2825, a MyD88 dimerisation inhibitor. Molecules 25(18):4322
doi: 10.3390/molecules25184322
pubmed: 32967164
pmcid: 7570868
Glocker EO et al (2009) Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 361(21):2033–2045
doi: 10.1056/NEJMoa0907206
pubmed: 19890111
pmcid: 2787406
Fagerberg L et al (2014) Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics 13(2):397–406
doi: 10.1074/mcp.M113.035600
pubmed: 24309898