Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia
| Autor: | Mieke Metzemaekers, Susan M. Schlenner, Emanuela Pasciuto, Patrick Matthys, Stephanie Humblet-Baron, Elien Smeets, Adrian Liston, Axelle Kerstens, Joost Schymkowitz, Laura Seldeslachts, Paul Proost, Sarah Haßdenteufel, Carine Wouters, Frank Claessens, Julika Neumann, Teresa Prezzemolo, Nancy Boeckx, Vasiliki Lagou, John S. Barber, Frederic Rousseau, Bert Malengier-Devlies, Rob van der Kant, Erika Van Nieuwenhove, Christine Devalck, Isabelle Meyts, Sven Lang, Richard Zimmermann, Daniele Di Marino, Sebastian Munck, Mathijs Willemsen |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Myeloid Neutrophils CD34 G-CSF Granulocyte colony-stimulating factor Antigens CD34 Chromosome Disorders whole exome sequencing 0302 clinical medicine BiP Immunoglobulin heavy chain binding protein Immunologie Immunology and Allergy Missense mutation Congenital Bone Marrow Failure Syndromes Exome sequencing Genes Dominant Severe congenital neutropenia CHOP CCAAT/enhancer-binding protein homologous protein unfolded protein response SEC61A1 3. Good health Transport protein Pedigree medicine.anatomical_structure TM Transmembrane helix NE Neutrophil elastase 030220 oncology & carcinogenesis endoplasmic reticulum stress Female Single-Cell Analysis CVID Common variable immune deficiency Allergie et immunopathologie Neutropenia WT Wild-type Immunology HL-60 Cells Biology qPCR Quantitative polymerase chain reaction 03 medical and health sciences Young Adult ER Endoplasmic reticulum Downregulation and upregulation Exome Sequencing medicine Humans SCN Severe congenital neutropenia ADTKD Autosomal dominant tubulointerstitial kidney disease UPR Unfolded protein response Endoplasmic reticulum Translational and Clinical Immunology DMSO Dimethyl sulfoxide Molecular biology 030104 developmental biology Mutation Unfolded protein response SEC Translocation Channels |
| Zdroj: | Journal of allergy and clinical immunology The Journal of Allergy and Clinical Immunology Journal of Allergy and Clinical Immunology |
| Popis: | Background: The molecular cause of severe congenital neutropenia (SCN) is unknown in 30% to 50% of patients. SEC61A1 encodes the α-subunit of the Sec61 complex, which governs endoplasmic reticulum protein transport and passive calcium leakage. Recently, mutations in SEC61A1 were reported to be pathogenic in common variable immunodeficiency and glomerulocystic kidney disease. Objective: Our aim was to expand the spectrum of SEC61A1-mediated disease to include autosomal dominant SCN. Methods: Whole exome sequencing findings were validated, and reported mutations were compared by Western blotting, Ca2+ flux assays, differentiation of transduced HL-60 cells, in vitro differentiation of primary CD34 cells, quantitative PCR for unfolded protein response (UPR) genes, and single-cell RNA sequencing on whole bone marrow. Results: We identified a novel de novo missense mutation in SEC61A1 (c.A275G;p.Q92R) in a patient with SCN who was born to nonconsanguineous Belgian parents. The mutation results in diminished protein expression, disturbed protein translocation, and an increase in calcium leakage from the endoplasmic reticulum. In vitro differentiation of CD34+ cells recapitulated the patient's clinical arrest in granulopoiesis. The impact of Q92R-Sec61α1 on neutrophil maturation was validated by using HL-60 cells, in which transduction reduced differentiation into CD11b+CD16+ cells. A potential mechanism for this defect is the uncontrolled initiation of the unfolded protein stress response, with single-cell analysis of primary bone marrow revealing perturbed UPR in myeloid precursors and in vitro differentiation of primary CD34+ cells revealing upregulation of CCAAT/enhancer-binding protein homologous protein and immunoglobulin heavy chain binding protein UPR-response genes. Conclusion: Specific mutations in SEC61A1 cause SCN through dysregulation of the UPR. SCOPUS: ar.j info:eu-repo/semantics/published |
| Databáze: | OpenAIRE |
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