Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome PMID: 29805043

Target-related Cytokines

2026-09-23

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.

M Cecilia Poli ¹ , Frédéric Ebstein ² , Sarah K Nicholas ³ , Marietta M de Guzman ³ , Lisa R Forbes ⁴ , Ivan K Chinn ³ , Emily M Mace ³ , Tiphanie P Vogel ³ , Alexandre F Carisey ³ , Felipe Benavides ⁵ , Zeynep H Coban-Akdemir ⁶ , Richard A Gibbs ⁷ , Shalini N Jhangiani ⁸ , Donna M Muzny ⁸ , Claudia M B Carvalho ⁶ , Deborah A Schady ⁹ , Mahim Jain ⁶ , Jill A Rosenfeld ⁶ , Lisa Emrick ¹⁰ , Richard A Lewis ¹¹ , Brendan Lee ⁶ , Undiagnosed Diseases Network members , Barbara A Zieba ² , Sébastien Küry ¹² , Elke Krüger ² , James R Lupski ¹³ , Bret L Bostwick ¹⁴ , Jordan S Orange ¹⁵

Affiliations

1. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Division of Pediatric Immunology, Allergy, and Rheumatology, Houston, TX 77030, USA; Instituto de Ciencias e Innovación en Medicina, Universidad del Desarrollo, Clínica Alemana de Santiago, RM 7590943, Chile.
2. Universitätsmedizin Greifswald, Institut für Medizinische Biochemie und Molekularbiologie, 17475 Greifswald, Germany.
3. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Division of Pediatric Immunology, Allergy, and Rheumatology, Houston, TX 77030, USA.
4. Texas Children's Hospital, Division of Pediatric Immunology, Allergy, and Rheumatology, Houston, TX 77030, USA.
5. Instituto de Ciencias e Innovación en Medicina, Universidad del Desarrollo, Clínica Alemana de Santiago, RM 7590943, Chile.
6. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
7. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
8. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
9. Texas Children's Hospital, Department of Pathology and Immunology, Houston, TX 77030, USA.
10. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
11. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA.
12. Centre Hospitalier Universitaire de Nantes Hôtel-Dieu, Institut de Biologie, Service de Génétique Médicale, Laboratoire de Génétique Moléculaire, 44093 Nantes Cedex 1, France.
13. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
14. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
15. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Division of Pediatric Immunology, Allergy, and Rheumatology, Houston, TX 77030, USA. Electronic address: [email protected].

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.

Keywords

PID; POMP; POMP-related autoinflammation and immune dysregulation disease; PRAID; autoinflammatory syndrome; core particle proteasome 20S; dominant negative; interferonopathy; nonsense-mediated decay; primary immune deficiency.