Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation

J Allergy Clin Immunol. 2020 Jul;146(1):192-202. doi: 10.1016/j.jaci.2019.12.004. Epub 2019 Dec 17.


Background: The gene AK2 encodes the phosphotransferase adenylate kinase 2 (AK2). Human variants in AK2 cause reticular dysgenesis, a severe combined immunodeficiency with agranulocytosis, lymphopenia, and sensorineural deafness that requires hematopoietic stem cell transplantation for survival.

Objective: We investigated the mechanisms underlying recurrent sinopulmonary infections and hypogammaglobulinemia in 15 patients, ranging from 3 to 34 years of age, from 9 kindreds. Only 2 patients, both of whom had mildly impaired T-cell proliferation, each had a single clinically significant opportunistic infection.

Methods: Patient cells were studied with next-generation DNA sequencing, tandem mass spectrometry, and assays of lymphocyte and mitochondrial function.

Results: We identified 2 different homozygous variants in AK2. AK2G100S and AK2A182D permit residual protein expression, enzymatic activity, and normal numbers of neutrophils and lymphocytes. All but 1 patient had intact hearing. The patients' B cells had severely impaired proliferation and in vitro immunoglobulin secretion. With activation, the patients' B cells exhibited defective mitochondrial respiration and impaired regulation of mitochondrial membrane potential and quality. Although activated T cells from the patients with opportunistic infections demonstrated impaired mitochondrial function, the mitochondrial quality in T cells was preserved. Consistent with the capacity of activated T cells to utilize nonmitochondrial metabolism, these findings revealed a less strict cellular dependence of T-cell function on AK2 activity. Chemical inhibition of ATP synthesis in control T and B cells similarly demonstrated the greater dependency of B cells on mitochondrial function.

Conclusions: Our patients demonstrate the in vivo sequelae of the cell-specific requirements for the functions of AK2 and mitochondria, particularly in B-cell activation and antibody production.

Keywords: AK2; B cells; adenylate kinase 2; common variable immunodeficiency; hypogammaglobulinemia; mitochondria; oxidative phosphorylation; primary immunodeficiencies.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / genetics*
  • Adenylate Kinase / immunology
  • Adult
  • Amino Acid Substitution
  • B-Lymphocytes / immunology*
  • Child
  • Child, Preschool
  • Female
  • Homozygote*
  • Humans
  • Lymphocyte Activation / genetics*
  • Male
  • Mutation, Missense*
  • Severe Combined Immunodeficiency / genetics*
  • Severe Combined Immunodeficiency / immunology
  • T-Lymphocytes / immunology


  • Adenylate Kinase
  • adenylate kinase 2