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HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease)


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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Figure 1: Haplotypes on chromosome 1q.
Figure 2: Bone marrow phenotype, HAX1 genotype and HAX1 expression.
Figure 3: Apoptosis and mitochondrial membrane potential in HAX1-deficient granulocytes.
Figure 4: Reconstitution of ΔΨm in myeloid progenitor cells and fibroblasts after retroviral HAX1 gene transfer.

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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.

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Authors and Affiliations



C.K. designed and directed the study; obtained clinical samples; taught and supervised G.A., I.S., K.B., C.R. and G.B.; provided laboratory resources and wrote the manuscript with help from B.G. and A.A.S. The manuscript was then reviewed and approved by all authors. M. Grudzien did the genotyping for linkage analysis and sequenced candidate genes. G.A. performed all gene transfer studies and functional assays on myeloid cells and fibroblasts. M. Germeshausen sequenced HAX1, ELA2 and CSFR3 and comprehensively analyzed genetic data. I.S. discovered the first HAX1 mutation and performed sequencing and protein blotting. A.A.S. chose markers to genotype in the linkage region and performed linkage analysis computations. K.B. performed functional immunological assays. C.R. performed functional neutrophil studies and taught G.A. C.Z. cared for patients and collected and curated data in the SCN patient registry. B.S. collected and curated data in the SCN patient registry. N.R. treated patients in Iran and ascertained their samples for this study. G.B. performed functional neutrophil studies and sequenced candidate genes. G.C. and J.-I.H. initiated the Swedish Kostmann family project; G.C. treated the patients, and J.-I.H. and J.P. supervised the project with the support of B.F. N.D. was responsible for Swedish Kostmann gene studies. M.M. sequenced genomic samples from the Kostmann family. B.G. provided laboratory resources, organized patient samples, supervised M. Grudzien and assisted A.A.S. K.W. provided laboratory resources and resources for SCN registry and helped to initiate and carry out the study. M. Grudzien and G.A. contributed equally to this work and are considered acquo loco.

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Correspondence to Christoph Klein.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Germline HAX1 mutation in members of the original Kostmann pedigree. (PDF 433 kb)

Supplementary Fig. 2

Increased apoptosis and enzymatic caspase 3/7 activity in HAX1-deficient granulocytes. (PDF 965 kb)

Supplementary Fig. 3

Increased loss of mitochondrial membrane potential ΔΨm in HAX1-deficient fibroblasts. (PDF 743 kb)

Supplementary Table 1

Immunological analysis of HAX1-deficient patients. (PDF 65 kb)

Supplementary Table 2

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).

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