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

Chou, Janet, Alazami, Anas M., Jaber, Faris, Hoyos-Bachiloglu, Rodrigo, Jones, Jennifer, Weeks, Sabrina, Alosaimi, Mohammed F., Bainter, Wayne, Cangemi, Brittney, Badran, Yousef R., Mohammed, Reem, Alroqi, Fayhan, Almutairi, Abduarahman, Al-Onazi, Noufa, AlAjaji, Sulaiman, Al-Saud, Bander, Arnaout, Rand, Elkins, Megan, Devana, Sridevi, Imperial, Juliet, Li, Betty, Drexhage, Linnea, Rahman, Anas M. Abdel, Jacob, Minnie, Haddad, Hadi, Hanna-Wakim, Rima, Dbaibo, Ghassan, Massaad, Michel J., Dasouki, Majed, Mikhael, Raymond, Baz, Zeina, Geha, Raif S., and Al-Mousa, Hamoud (2020) Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B-cell activation. Journal of Allergy and Clinical Immunology, 146 (1). pp. 192-202.

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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.


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.


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


We identified 2 different homozygous variants in AK2. AK2(G100S) and AK2(A182D) 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.


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.

Item ID: 64955
Item Type: Article (Research - C1)
ISSN: 1097-6825
Keywords: AK2, adenylate kinase 2, hypogammaglobulinemia, mitochondria, oxidative phosphorylation, primary immunodeficiencies, B cells, common variable immunodeficiency
Copyright Information: © 2019 Published by Elsevier Inc. on behalf of the American Academy of Allergy,Asthma & Immunology
Funders: Perkin Fund, National Science, Technology and Innovation Plan program of Saudi Arabia (NSTIP)
Projects and Grants: 5K08AI116979-04, 1R01AI139633-01, NSTIP grant KACST 13-BIO-755-2, Saudi Human Genome Program
Date Deposited: 04 Nov 2020 07:48
FoR Codes: 32 BIOMEDICAL AND CLINICAL SCIENCES > 3204 Immunology > 320499 Immunology not elsewhere classified @ 100%
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