Autosomal recessive severe congenital neutropenia (SCN)1 constitutes a primary immunodeficiency syndrome associated with increased apoptosis in myeloid cells2,3, yet the underlying genetic defect remains unknown. Using a positional cloning approach and candidate gene evaluation, we identified a recurrent homozygous germline mutation in HAX1 in three pedigrees. After further molecular screening of individuals with SCN, we identified 19 additional affected individuals with homozygous HAX1 mutations, including three belonging to the original pedigree described by Kostmann1. HAX1 encodes the mitochondrial protein HAX1, which has been assigned functions in signal transduction4 and cytoskeletal control5,6. Here, we show that HAX1 is critical for maintaining the inner mitochondrial membrane potential and protecting against apoptosis in myeloid cells. Our findings suggest that HAX1 is a major regulator of myeloid homeostasis and underline the significance of genetic control of apoptosis in neutrophil development.
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We are indebted to the participants and their families and to M. Ballmaier and C. Reimers (Central Medical School Hannover, Flow Cytometry Laboratory) for their assistance. We thank all colleagues referring and registering patients at the International SCN Registry. We wish to acknowledge the genetic studies performed by M. Entesarian, K. Ericson and M. Nordenskjöld. Plasmid K83.pHCMV-GALVenv was a gift from C. Baum (Hannover Medical School). This study was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG-KliFo 110), by the German José Carreras Leukemia Foundation, by the Bundesministerium für Bildung und Forschung (Congenital Bone Marrow Failure Syndromes) and in part by the Intramural Research program of the US National Institutes of Health, National Library of Medicine.
The authors declare no competing financial interests.
Germline HAX1 mutation in members of the original Kostmann pedigree. (PDF 433 kb)
Increased apoptosis and enzymatic caspase 3/7 activity in HAX1-deficient granulocytes. (PDF 965 kb)
Increased loss of mitochondrial membrane potential ΔΨm in HAX1-deficient fibroblasts. (PDF 743 kb)
Immunological analysis of HAX1-deficient patients. (PDF 65 kb)
HAX2 genomic PCR primers and conditions. (PDF 52 kb)
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Klein, C., Grudzien, M., Appaswamy, G. et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet 39, 86–92 (2007). https://doi.org/10.1038/ng1940
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