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 Authors
JournalAm J Hum Genet
Volume102
Issue6
Pagination1126-1142
Date Published2018 Jun 07
ISSN1537-6605
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.

DOI10.1016/j.ajhg.2018.04.010
Alternate JournalAm. J. Hum. Genet.
PubMed ID29805043
PubMed Central IDPMC5992134
Grant ListR01 AI120989 / AI / NIAID NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
U01 HG007709 / HG / NHGRI NIH HHS / United States