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

TitleHeterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome.
Publication TypeJournal Article
Year of Publication2018
AuthorsM Poli, C, 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, Zieba, BA, Küry, S, Krüger, E, Lupski, JR, Bostwick, BL, Orange, JS
Corporate AuthorsUndiagnosed Diseases Network members
JournalAm J Hum Genet
Date Published2018 Jun 07
KeywordsBase Sequence, Cell Line, Endoplasmic Reticulum Stress, Exons, Family, Frameshift Mutation, Genetic Predisposition to Disease, Heterozygote, Humans, Immunologic Deficiency Syndromes, Immunophenotyping, Infant, Newborn, Inflammation, Interferon Type I, Male, Molecular Chaperones, Mutant Proteins, Mutation, Nonsense Mediated mRNA Decay, Phenotype, Proteasome Endopeptidase Complex, RNA, Messenger, Syndrome, Unfolded Protein Response

The 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.

Alternate JournalAm J Hum Genet
PubMed ID29805043
PubMed Central IDPMC5992134
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
U01 HG007709 / HG / NHGRI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
R01 AI120989 / AI / NIAID NIH HHS / United States

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