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要旨

We identified a new homozygous stop-codon mutation in the COPZ1 gene (p.Q141X) in two siblings with severe neutropenia and neurological developmental delay. COPZ1 is a member of the coatomer protein complex I (COPI) regulating intracellular trafficking of proteins. CRISPR/Cas9-mediated introduction of the stop-codon mutation at the position p.Q141X in COPZ1 in healthy donors` cord blood hematopoietic stem cells (HSPCs) and iPSCs led to defective granulocytic differentiation in vitro. Additionally, copz1 mutant zebrafish embryos produced significantly fewer neutrophils than their control counterparts. These findings were in line with hyperactivated unfolded protein response (UPR) and elevated autophagy in the myeloid cell line NB4 after introduction of the truncated mutation in COPZ1. COPZ1 is ubiquitously expressed, while its paralogous gene, COPZ2, is absent in the blood and the brain. Interestingly, the rescue of COPZ1 mutated HSPCs with COPZ2 corrected the defective granulopoiesis. Thus, we describe a new severe congenital neutropenia syndrome caused by autosomal recessive COPZ1 mutations with downstream UPR and autophagy activation.