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Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation

2021Journal article Open access
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dc.contributor.authorOuahed, J
dc.contributor.authorKelsen, JR
dc.contributor.authorSpessott, WA
dc.contributor.authorKooshesh, K
dc.contributor.authorSanmillan, ML
dc.contributor.authorDawany, N
dc.contributor.authorSullivan, KE
dc.contributor.authorHamilton, KE
dc.contributor.authorSlowik, V
dc.contributor.authorNejentsev, S
dc.contributor.authorFarela Neves, J
dc.contributor.authorFlores, H
dc.contributor.authorChung, WK
dc.contributor.authorWilson, A
dc.contributor.authorAnyane-Yeboa, K
dc.contributor.authorWou, K
dc.contributor.authorJain, P
dc.contributor.authorField, M
dc.contributor.authorTollefson, S
dc.contributor.authorDent, MH
dc.contributor.authorLi, D
dc.contributor.authorNaito, T
dc.contributor.authorMcGovern, DPH
dc.contributor.authorKwong, AC
dc.contributor.authorTaliaferro, F
dc.contributor.authorOrdovas-Montanes, J
dc.contributor.authorHorwitz, BH
dc.contributor.authorKotlarz, D
dc.contributor.authorKlein, C
dc.contributor.authorEvans, J
dc.contributor.authorDorsey, J
dc.contributor.authorWarner, N
dc.contributor.authorElkadri, A
dc.contributor.authorMuise, AM
dc.contributor.authorGoldsmith, J
dc.contributor.authorThompson, B
dc.contributor.authorEngelhardt, KR
dc.contributor.authorCant, AJ
dc.contributor.authorHambleton, S
dc.contributor.authorBarclay, A
dc.contributor.authorToth-Petroczy, A
dc.contributor.authorVuzman, D
dc.contributor.authorCarmichael, N
dc.contributor.authorBodea, C
dc.contributor.authorCassa, CA
dc.contributor.authorDevoto, M
dc.contributor.authorMaas, RL
dc.contributor.authorBehrens, EM
dc.contributor.authorGiraudo, CG
dc.contributor.authorSnapper, SB
dc.date.accessioned2023-11-03T12:08:13Z
dc.date.available2023-11-03T12:08:13Z
dc.date.issued2021
dc.description.abstractBackground and aims: Very early onset inflammatory bowel disease [VEOIBD] is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic aetiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation. Methods: Whole exome sequencing was performed on five families with ten patients who presented with a similar constellation of symptoms including medically refractory infantile-onset IBD, bilateral sensorineural hearing loss and, in the majority, recurrent infections. Genetic aetiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on peripheral blood mononuclear cells and functional studies with epithelial cell lines were employed. Results: In each of the ten patients, we identified damaging heterozygous or biallelic variants in the Syntaxin-Binding Protein 3 gene [STXBP3], a protein known to regulate intracellular vesicular trafficking in the syntaxin-binding protein family of molecules, but not associated to date with either VEOIBD or sensorineural hearing loss. These mutations interfere with either intron splicing or protein stability and lead to reduced STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity. Conclusion: Overall, we describe a novel genetic syndrome and identify a critical role for STXBP3 in VEOIBD, sensorineural hearing loss and immune dysregulation.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationJ Crohns Colitis . 2021 Nov 8;15(11):1908-1919pt_PT
dc.identifier.doi10.1093/ecco-jcc/jjab077pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.17/4734
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherOxford University Presspt_PT
dc.subjectAge of Onsetpt_PT
dc.subjectExome Sequencingpt_PT
dc.subjectGenetic Variation / geneticspt_PT
dc.subjectHearing Loss, Sensorineural / epidemiologypt_PT
dc.subjectHearing Loss, Sensorineural / genetics*pt_PT
dc.subjectImmune System Diseases / epidemiologypt_PT
dc.subjectImmune System Diseases / genetics*pt_PT
dc.subjectInfant, Newbornpt_PT
dc.subjectInflammatory Bowel Diseases / epidemiologypt_PT
dc.subjectInflammatory Bowel Diseases / genetics*pt_PT
dc.subjectQa-SNARE Proteins / analysis*pt_PT
dc.subjectQa-SNARE Proteins / geneticspt_PT
dc.subjectHDE GAS PEDpt_PT
dc.subjectHDE INF PEDpt_PT
dc.titleVariants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulationpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage1919pt_PT
oaire.citation.issue11pt_PT
oaire.citation.startPage1908pt_PT
oaire.citation.titleJournal of Crohn's and Colitispt_PT
oaire.citation.volume15pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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