Abstract
Human severe combined immunodeficiencies (SCID) are phenotypically and genotypically heterogeneous diseases1. Reticular dysgenesis is the most severe form of inborn SCID. It is characterized by absence of granulocytes and almost complete deficiency of lymphocytes in peripheral blood, hypoplasia of the thymus and secondary lymphoid organs, and lack of innate and adaptive humoral and cellular immune functions, leading to fatal septicemia within days after birth2,3,4,5,6,7,8. In bone marrow of individuals with reticular dysgenesis, myeloid differentiation is blocked at the promyelocytic stage, whereas erythro- and megakaryocytic maturation is generally normal. These features exclude a defect in hematopoietic stem cells but point to a unique aberration of the myelo-lymphoid lineages. The dramatic clinical course of reticular dysgenesis and its unique hematological phenotype have spurred interest in the unknown genetic basis of this syndrome. Here we show that the gene encoding the mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2) is mutated in individuals with reticular dysgenesis. Knockdown of zebrafish ak2 also leads to aberrant leukocyte development, stressing the evolutionarily conserved role of AK2. Our results provide in vivo evidence for AK2 selectivity in leukocyte differentiation. These observations suggest that reticular dysgenesis is the first example of a human immunodeficiency syndrome that is causally linked to energy metabolism and that can therefore be classified as a mitochondriopathy.
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Acknowledgements
We acknowledge the technical assistance of S. Braun, I. Janz, K. Heinrich, T. Kersten and S. Radecke. We are grateful to M. Schorpp for helpful advice. These studies were supported by the German Red Cross Blood Service Baden-Wuerttemberg-Hessen to K.S., the Deutsche Forschungsgemeinschaft (SFB620) and the Max-Planck Society to T.B.
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U.P., M.H., T.B. and K.S. designed the study. M.H., A.S. and W.F. cared for the subjects, collected clinical data and performed immunophenotyping. I.H. and T.B. contributed the zebrafish in situ hybridizations. K.H. performed and K.H. and K.S. analyzed the chip experiments. U.P., M.H., E.-M.R. and K.S. worked on the RT-PCR screen, the molecular and expression data and on mitochondrial analyses. C.F. performed the apoptosis, mitochondrial membrane potential and ROS assays. T.F.B. collected the immunohistochemistry data. E.-M.R. and M.T.R. did the FACS sorting. U.P., M.H., T.B. and K.S. wrote the paper.
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Pannicke, U., Hönig, M., Hess, I. et al. Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nat Genet 41, 101–105 (2009). https://doi.org/10.1038/ng.265
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DOI: https://doi.org/10.1038/ng.265
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