1. Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome.
- Author
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Poli 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, Zieba BA, Küry S, Krüger E, Lupski JR, Bostwick BL, and Orange JS
- Subjects
- Base Sequence, Cell Line, Endoplasmic Reticulum Stress, Exons genetics, Family, Frameshift Mutation genetics, Heterozygote, Humans, Immunologic Deficiency Syndromes genetics, Immunophenotyping, Infant, Newborn, Inflammation pathology, Interferon Type I metabolism, Male, Mutant Proteins metabolism, Phenotype, Proteasome Endopeptidase Complex metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Syndrome, Unfolded Protein Response, Genetic Predisposition to Disease, Molecular Chaperones genetics, Mutation genetics, Nonsense Mediated mRNA Decay genetics
- Abstract
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., (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
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