Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome

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dc.contributor.authorPoli, Cecilia
dc.contributor.authorEbstein, Frédéric
dc.contributor.authorNicholas, Sarah K.
dc.contributor.authorGuzman, Marietta M. de
dc.contributor.authorForbes, Lisa R.
dc.contributor.authorChinn, Ivan K.
dc.contributor.authorMace, Emily M.
dc.contributor.authorVogel, Tiphanie P.
dc.contributor.authorCarisey, Alexandre F.
dc.contributor.authorBenavides, Felipe
dc.contributor.authorCoban-Akdemir, Zeynep H.
dc.contributor.authorGibbs, Richard A.
dc.contributor.authorJhangiani, Shalini N.
dc.contributor.authorMuzny, Donna M.
dc.contributor.authorCarvalho, Claudia M. B.
dc.contributor.authorSchady, Deborah A.
dc.contributor.authorJain, Mahim
dc.contributor.authorRosenfeld, Jill A .
dc.contributor.authorEmrick, Lisa
dc.contributor.authorLewis, Richard A.
dc.contributor.authorLee, Brendan
dc.contributor.authorUndiagnosed Diseases Network members
dc.contributor.authorZieba, Barbara A.
dc.contributor.authorKüry, Sébastien
dc.contributor.authorKrüger, Elke
dc.contributor.authorLupski, James R.
dc.contributor.authorBostwick, Bret L.
dc.contributor.authorOrange, Jordan S.
dc.date.accessioned2022-05-27T23:11:39Z
dc.date.available2022-05-27T23:11:39Z
dc.date.issued2018
dc.description.abstractThe proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that perturbs proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.es
dc.description.versionVersión Publicadaes
dc.identifier.citationPoli MC, Ebstein F, Nicholas SK, de Guzman MM, Forbes LR, Chinn IK, Mace EM, Vogel TP, Carisey AF, Benavides F, Coban-Akdemir ZH, Gibbs RA, Jhangiani SN, Muzny DM, Carvalho CMB, Schady DA, Jain M, Rosenfeld JA, Emrick L, Lewis RA, Lee B; Undiagnosed Diseases Network members, Zieba BA, Küry S, Krüger E, Lupski JR, Bostwick BL, Orange JS. Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome. Am J Hum Genet. 2018 Jun 7;102(6):1126-1142. doi: 10.1016/j.ajhg.2018.04.010. Epub 2018 May 24.es
dc.identifier.urihttps://doi.org/10.1016/j.ajhg.2018.04.010es
dc.identifier.urihttp://hdl.handle.net/11447/6152
dc.language.isoenes
dc.subjectPIDes
dc.subjectPOMPes
dc.subjectPOMP-related autoinflammation and immune dysregulation diseasees
dc.subjectPRAIDes
dc.subjectAutoinflammatory syndromees
dc.subjectCore particle proteasome 20Ses
dc.subjectDominant negativees
dc.subjectInterferonopathyes
dc.subjectNonsense-mediated decayes
dc.subjectPrimary immune deficiencyes
dc.titleHeterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndromees
dc.typeArticlees
dcterms.sourceThe American Journal of Human Geneticses

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