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

abstractWe 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.