biostudies-literatureZakrzewski PMedical Research FoundationGW4-CAT Wellcome Trust Clinical PhD fellowshipNHS Blood and Transplant R&D grantNIHR BTRU in partnership with NHSBTBarth Syndrome FoundationBristol and Weston Hospitals CharityCRUK Scotland Institute core fundingWellcome Trust Dynamic Cell PhD studentshipWellcome TrustNHS Blood and Transplant R&D grantMedical Research Foundation (MRF)1590-1619https://www.ebi.ac.uk/biostudies/studies/S-EPMC11933368biostudies-literatureUnknown26(6)Barth syndrome (BTHS) is a rare genetic disease caused by mutations in the TAFAZZIN gene. It is characterized by neutropenia, cardiomyopathy and skeletal myopathy. Neutropenia in BTHS is associated with life-threatening infections, yet there is little understanding of the molecular and physiological causes of this phenomenon. We combined bone marrow analysis, CRISPR/Cas9 genome editing in hematopoietic stem cells and functional characterization of circulating BTHS patient neutrophils to investigate the role of TAFAZZIN in neutrophils and their progenitors. We demonstrate a partial cell intrinsic differentiation defect, along with a dysregulated neutrophil inflammatory response in BTHS, including elevated degranulation and formation of neutrophil extracellular traps (NETs) in response to caEMBO reportsTafazzin regulates neutrophil maturation and inflammatory response.PMC11933368IS-BTU-1214-10032MR/R02149X/1A31287WP15-05Zakrzewski PAmulic BGroves SJToye AMSteward CCela DStrathdee DNobbs AHGibbs WFleming KPike TAnderson ERoberts KRice CMPonce-Garcia FMfalseTafazzin regulates neutrophil maturation and inflammatory response.Barth syndrome (BTHS) is a rare genetic disease caused by mutations in the TAFAZZIN gene. It is characterized by neutropenia, cardiomyopathy and skeletal myopathy. Neutropenia in BTHS is associated with life-threatening infections, yet there is little understanding of the molecular and physiological causes of this phenomenon. We combined bone marrow analysis, CRISPR/Cas9 genome editing in hematopoietic stem cells and functional characterization of circulating BTHS patient neutrophils to investigate the role of TAFAZZIN in neutrophils and their progenitors. We demonstrate a partial cell intrinsic differentiation defect, along with a dysregulated neutrophil inflammatory response in BTHS, including elevated degranulation and formation of neutrophil extracellular traps (NETs) in response to ca2025-01-01T00:00:00Z2025 Mar2026-06-02T21:12:32.111Z2026-05-29T03:06:29.046ZS-EPMC119333683996223110.1038/s44319-025-00393-w