title: Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2.
abstract: 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.
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pannicke
authors.forename: Manfred
authors.initials: M
authors.lastname: Hönig
authors.forename: Isabell
authors.initials: I
authors.lastname: Hess
authors.forename: Claudia
authors.initials: C
authors.lastname: Friesen
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Holzmann
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Rump
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Barth
authors.forename: Markus T
authors.initials: MT
authors.lastname: Rojewski
authors.forename: Ansgar
authors.initials: A
authors.lastname: Schulz
authors.forename: Thomas
authors.initials: T
authors.lastname: Boehm
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Friedrich
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
mesh_terms: D000263:Adenylate Kinase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000201:enzymology / Q000473:pathology; D002460:Cell Line; D004625:Embryo, Nonmammalian / Q000201:enzymology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000201:enzymology*; D009154:Mutation / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016511:Severe Combined Immunodeficiency / Q000201:enzymology* / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics*
chemical_list: D007527:Isoenzymes; D017382:Reactive Oxygen Species; D000263:Adenylate Kinase; C110938:adenylate kinase 2