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Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2


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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Figure 1: AK2 mutations and RNA and protein analyses in individuals with reticular dysgenesis.
Figure 2: Bone marrow mononuclear cell (BM MNC) and peripheral blood cell (PBC) AK expression.
Figure 3: Phenotype of ak2 zebrafish morphants.
Figure 4: Apoptosis, mitochondrial transmembrane potential and ROS analyses in fibroblasts of individuals with reticular dysgenesis.

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  1. Geha, R.S. et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J. Allergy Clin. Immunol. 120, 776–794 (2007).

    Article  Google Scholar 

  2. Alonso, K., Dew, J.M. & Starke, W.R. Thymic alymphoplasia and congenital aleukocytosis (reticular dysgenesia). Arch. Pathol. 94, 179–183 (1972).

    CAS  PubMed  Google Scholar 

  3. de Vaal, O. & Seynhaeve, V. Reticular dysgenesia. Lancet 2, 1123–1125 (1959).

    Article  CAS  Google Scholar 

  4. Emile, J.F., Durandy, A., Le Deist, F., Fischer, A. & Brousse, N. Epidermal Langerhans' cells in children with primary T-cell immune deficiencies. J. Pathol. 183, 70–74 (1997).

    Article  CAS  Google Scholar 

  5. Espanol, T. et al. Reticular dysgenesis: report of two brothers. Clin. Exp. Immunol. 38, 615–620 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Gitlin, D., Vawter, G. & Craig, J.M. Thymic alymphoplasia and congenital aleukocytosis. Pediatrics 33, 184–192 (1964).

    CAS  PubMed  Google Scholar 

  7. Haas, R.J. et al. Congenital immunodeficiency and agranulocytosis (reticular dysgenesia). Acta Paediatr. Scand. 66, 279–283 (1977).

    Article  CAS  Google Scholar 

  8. Ownby, D.R., Pizzo, S., Blackmon, L., Gall, S.A. & Buckley, R.H. Severe combined immunodeficiency with leukopenia (reticular dysgenesis) in siblings: immunologic and histopathologic findings. J. Pediatr. 89, 382–387 (1976).

    Article  CAS  Google Scholar 

  9. DiMauro, S. & Schon, E.A. Mitochondrial respiratory-chain diseases. N. Engl. J. Med. 348, 2656–2668 (2003).

    Article  CAS  Google Scholar 

  10. Wallace, D.C. Mouse models for mitochondrial disease. Am. J. Med. Genet. 106, 71–93 (2001).

    Article  CAS  Google Scholar 

  11. Dzeja, P.P. & Terzic, A. Phosphotransfer networks and cellular energetics. J. Exp. Biol. 206, 2039–2047 (2003).

    Article  CAS  Google Scholar 

  12. Schlauderer, G.J., Proba, K. & Schulz, G.E. Structure of a mutant adenylate kinase ligated with an ATP-analogue showing domain closure over ATP. J. Mol. Biol. 256, 223–227 (1996).

    Article  CAS  Google Scholar 

  13. Small, T.N. et al. Association of reticular dysgenesis (thymic alymphoplasia and congenital aleukocytosis) with bilateral sensorineural deafness. J. Pediatr. 135, 387–389 (1999).

    Article  CAS  Google Scholar 

  14. Chandra, D. et al. Intracellular nucleotides act as critical prosurvival factors by binding to cytochrome C and inhibiting apoptosome. Cell 125, 1333–1346 (2006).

    Article  CAS  Google Scholar 

  15. Riedl, S.J., Li, W., Chao, Y., Schwarzenbacher, R. & Shi, Y. Structure of the apoptotic protease-activating factor 1 bound to ADP. Nature 434, 926–933 (2005).

    Article  CAS  Google Scholar 

  16. Krishnan, K.J. et al. What causes mitochondrial DNA deletions in human cells? Nat. Genet. 40, 275–279 (2008).

    Article  CAS  Google Scholar 

  17. Müller, A., Holzmann, K. & Kestler, K. Visualization of genomic aberrations using Affymetrix SNP arrays. Bioinformatics 23, 496–497 (2007).

    Article  Google Scholar 

  18. Oxtoby, E. & Jowett, T. Cloning of the zebrafish krox-20 gene (krx-20) and its expression during hindbrain development. Nucleic Acids Res. 21, 1087–1095 (1993).

    Article  CAS  Google Scholar 

  19. Schorpp, M. et al. Conserved functions of Ikaros in vertebrate lymphocyte development: genetic evidence for distinct larval and adult phases of T cell development and two lineages of B cells in zebrafish. J. Immunol. 177, 2463–2476 (2006).

    Article  CAS  Google Scholar 

  20. Friesen, C., Kiess, Y. & Debatin, K.M. A critical role of glutathione in determining apoptosis sensitivity and resistance in leukemia cells. Cell Death Differ. 11, S73–S85 (2004).

    Article  CAS  Google Scholar 

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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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Correspondence to Klaus Schwarz.

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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).

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