AK2 encodes the phosphotransferase adenylate kinase 2 (AK2). Human mutations in AK2 cause reticular dysgenesis, a severe combined immunodeficiency with agranulocytosis, lymphopenia, fatal infections, and sensorineural deafness. We investigated the mechanisms underlying recurrent sino-pulmonary infections and hypogammaglobulinemia in 15 patients, ranging from 3 to 34 years of age, from nine kindreds.
Patient cells were studied with next-generation DNA sequencing, tandem mass spectrometry, and assays of lymphocyte and mitochondrial function.
We identified two different homozygous mutations in AK2. AK2G100S and AK2A182D permit residual protein expression, enzymatic activity, and normal numbers of neutrophils and lymphocytes. All but one patient have intact hearing. The patients’ B cells had severely impaired cell cycling and proliferation, reduced survival, and minimal in vitro immunoglobulin secretion. After activation, the patients’ B cells exhibit defective mitochondrial respiration and impaired clearance of dysfunctional mitochondria. The patients’ T cells demonstrated reduced diversity in Vβ usage in CD4+ and CD8+ T cells and impaired proliferation to antigens. However, in contrast to severely defective B cells function, the patients’ T cell proliferation to phytohemagglutinin was partially impaired in only 3 patients and intact in the remaining patients studied. These findings are consistent with the patients’ limited susceptibility to opportunistic infections and suggest a less strict cellular dependence of T cell function on AK2 activity.
These AK2 hypomorphic mutations demonstrate the importance of mitochondrial function for B cell activation and antibody production.