A new severe congenital neutropenia syndrome associated with autosomal recessive <i>COPZ1</i> mutations
Abstract
Abstract We have identified a new inherited bone marrow failure syndrome with severe congenital neutropenia (CN) caused by autosomal recessive mutations in the coatomer protein complex I (COPI) subunit zeta 1 (COPZ1) gene. A stop-codon COPZ1 mutation and a missense (MS) mutation were found in 3 patients from 2 unrelated families. Although 2 affected siblings with a stop-codon COPZ1 mutation suffered from CN that involves other hematologic lineages and nonhematologic tissues, the patient with a MS COPZ1 mutation had isolated neutropenia. Both COPZ1 mutations were localized to a highly evolutionarily conserved region. The resulting truncated (TR) COPZ1 protein was predicted to display diminished interaction with its COPI complex partner, COPG1. These findings were consistent with the observed block in retrograde protein transport from the Golgi apparatus to the endoplasmic reticulum (ER) in human fibroblasts carrying TR COPZ1. Human CD34+ cells with TR or MS COPZ1 had significantly impaired granulocytic differentiation, and in zebrafish embryos, TR Copz1 also resulted in defective myelopoiesis. Intracellularly, TR COPZ1 downregulated JAK/STAT/CEBPE/G-CSFR signaling and hypoxia-responsive pathways, while inducing STING, interferon-stimulated genes, stimulating oxidative phosphorylation activity, and increasing reactive oxygen species levels in hematopoietic cells. MS COPZ1 deregulated interferon and JAK/STAT signaling but less than the TR protein. Finally, treatment with the small molecule HIF1α stabilizer IOX2 or transduction of cells with COPZ2 restored defective granulopoiesis in COPZ1-mutated human CD34+ cells, offering potential therapeutic options.
Article Details
Authors (29)
Natalia Borbaran Bravo
Ekaterina Deordieva
2Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
Larissa Doll
1Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Mohammad ElGamacy
1Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Benjamin Dannenmann
1Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Joana Azevedo
Alberto Iannuzzo
Selket Delafontaine
7Department of Microbiology, Immunology, and Transplantation, Laboratory for Inborn Errors of Immunity, KU Leuven, Leuven, Belgium
Moritz Lehners
Marius Kolodziej
10Natural and Medical Sciences Institute, University of Tuebingen, Reutlingen, Germany
Birte Hernandez Alvarez
Anna-Sophia Hellmuth
1Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Malte Ritter
1University Hospital Tübingen, Translational Oncology, Tübingen, Germany
Betül Findik
4Department of Hematology, Oncology, Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
Viktoria Zakharova
11National Medical Research Center for Endocrinology, Clinical Data Analysis Department, National Medical Research Center for Endocrinology, Moscow, Russia
Sandro Bräuning
1Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Sergey Kandabarau
1University Hospital Tübingen, Translational Oncology, Tübingen, Germany
Claudia Lengerke
Robert Feil
Isabelle Meyts
Jérôme Delon
Markus Templin
10Natural and Medical Sciences Institute, University of Tuebingen, Reutlingen, Germany
Marc Sturm
Olaf Riess
Institute of Medical Genetics and Applied Genomics, University of Tuebingen
Cornelia Zeidler
5University of Tubingen, Tubingen, Germany
Karl Welte
1University Hospital Tuebingen, Tuebingen, Germany
Anna Shcherbina
Maksim Klimiankou
1University Hospital Tübingen, Translational Oncology, Tübingen, Germany
Julia Skokowa