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

2018; Elsevier BV; Volume: 102; Issue: 6 Linguagem: Inglês

10.1016/j.ajhg.2018.04.010

1537-6605

M. Cecilia Poli, Frédéric Ebstein, Sarah K. Nicholas, Marietta M. de Guzman, Lisa R. Forbes, Iván K. Chinn, Emily M. Mace, Tiphanie P. Vogel, Alexandre F. Carisey, Felipe Benavides, Zeynep Coban‐Akdemir, Richard A. Gibbs, Shalini N. Jhangiani, Donna M. Muzny, Claudia M.B. Carvalho, Deborah Schady, Mahim Jain, Jill A. Rosenfeld, Lisa Emrick, Richard A. Lewis, Brendan Lee, Barbara A. Zieba, Sébastien Küry, Elke Krüger, James R. Lupski, Bret L. Bostwick, Jordan S. Orange,

Endoplasmic Reticulum Stress and Disease

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.