RESUMO
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.
Assuntos
Adenilato Quinase/genética , Linfócitos B/imunologia , Homozigoto , Ativação Linfocitária/genética , Mutação de Sentido Incorreto , Imunodeficiência Combinada Severa/genética , Adenilato Quinase/imunologia , Adulto , Substituição de Aminoácidos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Imunodeficiência Combinada Severa/imunologia , Linfócitos T/imunologiaAssuntos
Linfócitos B/imunologia , Fatores de Troca do Nucleotídeo Guanina/imunologia , Imunoglobulina E/imunologia , Fator de Transcrição STAT3/imunologia , Receptor Toll-Like 9/imunologia , Linfócitos B/efeitos dos fármacos , Antígenos CD40/imunologia , Células Cultivadas , Humanos , Switching de Imunoglobulina , Interleucina-4/farmacologia , Síndrome de Job/imunologia , Oligodesoxirribonucleotídeos/farmacologiaAssuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Homozigoto , Janus Quinase 3/deficiência , Mutação , Sítios de Splice de RNA , Alelos , Biomarcadores , Biópsia , Análise Mutacional de DNA , Feminino , Humanos , Janus Quinase 3/genética , Janus Quinase 3/metabolismo , Masculino , Linhagem , Fenótipo , Pele/metabolismo , Pele/patologiaRESUMO
ORAI1 is the pore-forming subunit of the calcium release-activated calcium channel responsible for calcium influx into cells triggered by endoplasmic reticulum store depletion. We report here a patient with severe combined immunodeficiency and absent store-operated calcium entry due to a novel mutation in ORAI1 that results in the expression of a C-terminally truncated protein that abolishes ORAI1 binding to STIM1.