A New Severe Congenital Neutropenia Syndrome Associated with Autosomal Recessive COPZ1 Mutations

• Autosomal recessive mutations in the COPZ1 gene encoding Coatomer Protein Complex I (COPI) Subunit Z 1 cause severe congenital neutropenia.

• Mutations in COPZ1 lead to defective granulocytic differentiation, which can be rescued by the activation of HIF1.

We have identified a new inherited bone marrow (BM) 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 mutation were found in three patients from two unrelated families. While two affected siblings with a stop-codon COPZ1 mutation suffered from congenital neutropenia (CN) that involves other hematological lineages, and non-hematological tissues, the patient with a missense COPZ1 mutation had isolated neutropenia. Both COPZ1 mutations were localized to a highly evolutionarily conserved region. The resulting truncated 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 to the ER in human fibroblasts carrying truncated COPZ1. Human CD34+ cells with truncated or missense COPZ1 had significantly impaired granulocytic differentiation and in zebrafish embryos, truncated Copz1 also resulted in defective myelopoiesis. Intracellularly, truncated 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 (ROS) levels in CD34+ cells. Missense COPZ1 deregulated interferon and JAK/STAT signaling but less than the truncated protein. Finally, treatment with the small molecule HIF1α activator IOX2 or transduction of cells with COPZ2 cDNA restored defective granulopoiesis in COPZ1-mutated CD34+ cells, offering potential therapeutic options.