A new severe congenital neutropenia syndrome associated with autosomal recessive COPZ1 mutations

Natalia Borbaran Bravo; Ekaterina Deordieva; Larissa Doll; Mohammad ElGamacy; Benjamin Dannenmann; Joana Azevedo; Alberto Iannuzzo; Selket Delafontaine; Moritz Lehners; Marius Kolodziej; Birte Hernandez Alvarez; Anna-Sophia Hellmuth; Malte Ritter; Betül Findik; Viktoria Zakharova; Sandro Bräuning; Sergey Kandabarau; Claudia Lengerke; Robert Feil; Isabelle Meyts; Jérôme Delon; Markus Templin; Marc Sturm; Olaf Rieß; Cornelia Zeidler; Karl Welte; Anna Shcherbina; Maksim Klimiankou; Julia Skokowa

doi:10.1182/blood.2023022576

Retour

A new severe congenital neutropenia syndrome associated with autosomal recessive COPZ1 mutations

Article de revue

Avec comité de lecture

A new severe congenital neutropenia syndrome associated with autosomal recessive COPZ1 mutations

Natalia Borbaran Bravo, Ekaterina Deordieva, Larissa Doll, Mohammad ElGamacy, Benjamin Dannenmann, Joana Azevedo, Alberto Iannuzzo, Selket Delafontaine, Moritz Lehners, Marius Kolodziej, …

Blood, Vol.145(20), pp.2317-2335

15/05/2025

DOI: https://doi.org/10.1182/blood.2023022576

PMID: 39642330

Résumé

Animals

Congenital Bone Marrow Failure Syndromes - genetics

Female

Humans

Mutation

Neutropenia - congenital

Neutropenia - genetics

Neutropenia - metabolism

Neutropenia - pathology

Pedigree

Signal Transduction

Zebrafish

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.

Indicateurs

1 Consultations de la notice

See more details

Détails

Titre: A new severe congenital neutropenia syndrome associated with autosomal recessive COPZ1 mutations
Créateurs - sans rôle: Natalia Borbaran Bravo - Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Ekaterina Deordieva - Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
Larissa Doll - Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Mohammad ElGamacy - Department of Protein Evolution, Max Planck Institute for Biology, Tuebingen, Germany
Benjamin Dannenmann - Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Joana Azevedo - Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Alberto Iannuzzo - Université Paris Cité, French National Centre for Scientific Research, INSERM, Institut Cochin, Paris, France
Selket Delafontaine - Department of Pediatrics, University Hospital Leuven, Leuven, Belgium
Moritz Lehners - Interfaculty Institute of Biochemistry, University of Tuebingen, Tuebingen, Germany
Marius Kolodziej - Natural and Medical Sciences Institute, University of Tuebingen, Reutlingen, Germany
Birte Hernandez Alvarez - Department of Protein Evolution, Max Planck Institute for Biology, Tuebingen, Germany
Anna-Sophia Hellmuth - Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Malte Ritter - Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Betül Findik - Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Viktoria Zakharova - National Medical Research Center for Endocrinology, Clinical Data Analysis Department, National Medical Research Center for Endocrinology, Moscow, Russia
Sandro Bräuning - Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Sergey Kandabarau - Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Claudia Lengerke - Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Robert Feil - Interfaculty Institute of Biochemistry, University of Tuebingen, Tuebingen, Germany
Isabelle Meyts - Department of Pediatrics, University Hospital Leuven, Leuven, Belgium
Jérôme Delon - Université Paris Cité
Markus Templin - Natural and Medical Sciences Institute, University of Tuebingen, Reutlingen, Germany
Marc Sturm - Institute of Medical Genetics and Applied Genomics, University Hospital Tuebingen, Tuebingen, Germany
Olaf Rieß - Institute of Medical Genetics and Applied Genomics, University Hospital Tuebingen, Tuebingen, Germany
Cornelia Zeidler - Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Karl Welte - Department of Pediatric Hematology and Oncology, University Children's Hospital Tuebingen, Tuebingen, Germany
Anna Shcherbina - Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
Maksim Klimiankou - Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Julia Skokowa - Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany
Détails de publication: Blood, Vol.145(20), pp.2317-2335
Note de subvention: R24 AI162637 / NIAID NIH HHS
Identifiants: 99154022609311
Unité académique: Institut de Génétique Moléculaire de Montpellier - IGMM
Langue: English
Type de ressource: Journal article