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Sökning: WFRF:(Boztug K)

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  • Klein, Christoph, et al. (författare)
  • HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease)
  • 2007
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 39:1, s. 86-92
  • Tidskriftsartikel (refereegranskat)abstract
    • Autosomal recessive severe congenital neutropenia (SCN) constitutes a primary immunodeficiency syndrome associated with increased apoptosis in myeloid cells, 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 Kostmann. HAX1 encodes the mitochondrial protein HAX1, which has been assigned functions in signal transduction and cytoskeletal control. 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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  • Serwas, N. K., et al. (författare)
  • CEBPE-mutant specific granule deficiency correlates with aberrant granule organization and substantial proteome alterations in neutrophils
  • 2018
  • Ingår i: Frontiers in Immunology. - 1664-3224. ; 9:MAR
  • Tidskriftsartikel (refereegranskat)abstract
    • Specific granule deficiency (SGD) is a rare disorder characterized by abnormal neutrophils evidenced by reduced granules, absence of granule proteins, and atypical bilobed nuclei. Mutations in CCAAT/enhancer-binding protein-e (CEBPE) are one molecular etiology of the disease. Although C/EBPe has been studied extensively, the impact of CEBPE mutations on neutrophil biology remains elusive. Here, we identified two SGD patients bearing a previously described heterozygous mutation (p.Val218Ala) in CEBPE. We took this rare opportunity to characterize SGD neutrophils in terms of granule distribution and protein content. Granules of patient neutrophils were clustered and polarized, suggesting that not only absence of specific granules but also defects affecting other granules contribute to the phenotype. Our analysis showed that remaining granules displayed mixed protein content and lacked several glycoepitopes. To further elucidate the impact of mutant CEBPE, we performed detailed proteomic analysis of SGD neutrophils. Beside an absence of several granule proteins in patient cells, we observed increased expression of members of the linker of nucleoskeleton and cytoskeleton complex (nesprin-2, vimentin, and lamin-B2), which control nuclear shape. This suggests that absence of these proteins in healthy individuals might be responsible for segmented shapes of neutrophilic nuclei. We further show that the heterozygous mutation p.Val218Ala in CEBPE causes SGD through prevention of nuclear localization of the protein product. In conclusion, we uncover that absence of nuclear C/EBPe impacts on spatiotemporal expression and subsequent distribution of several granule proteins and further on expression of proteins controlling nuclear shape. © 2018 Serwas, Huemer, Dieckmann, Mejstrikova, Garncarz, Litzman, Hoeger, Zapletal, Janda, Bennett, Kain, Kerjaschky and Boztug.
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  • Resultat 1-10 av 15
  • [1]2Nästa

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