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

Pannicke, U., Hönig, M., Hess, I., Friesen, C., Holzmann, K., Rump, E.M., Barth, T.F., Rojewski, M.T., Schulz, A., Boehm, T., Friedrich, W., and Schwarz, K.
Nature Genetics   41(1): 101-105 (Journal)
Registered Authors
Boehm, Tom, Hess, Isabell
MeSH Terms
  • Adenylate Kinase/genetics*
  • Adenylate Kinase/metabolism
  • Animals
  • Apoptosis
  • Bone Marrow Cells/enzymology
  • Bone Marrow Cells/pathology
  • Cell Line
  • Embryo, Nonmammalian/enzymology
  • Female
  • Fibroblasts/metabolism
  • Fibroblasts/pathology
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Isoenzymes/genetics*
  • Isoenzymes/metabolism
  • Leukocytes, Mononuclear/enzymology
  • Leukocytes, Mononuclear/pathology
  • Male
  • Membrane Potential, Mitochondrial
  • Mitochondria/enzymology*
  • Mutation/genetics*
  • Reactive Oxygen Species/metabolism
  • Severe Combined Immunodeficiency/enzymology*
  • Severe Combined Immunodeficiency/genetics*
  • Zebrafish/genetics*
19043417 Full text @ Nat. Genet.
Human severe combined immunodeficiencies (SCID) are phenotypically and genotypically heterogeneous diseases. 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 birth. 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.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes