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/imunologiaRESUMO
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.
Assuntos
Mutação , Proteínas de Neoplasias/genética , Proteína ORAI1/genética , Imunodeficiência Combinada Severa/genética , Molécula 1 de Interação Estromal/genética , Sequência de Bases , Exoma/genética , Evolução Fatal , Feminino , Células HEK293 , Homozigoto , Humanos , Lactente , Proteínas de Neoplasias/metabolismo , Proteína ORAI1/metabolismo , Ligação Proteica/genética , Análise de Sequência de DNA , Deleção de Sequência , Imunodeficiência Combinada Severa/metabolismo , Molécula 1 de Interação Estromal/metabolismoRESUMO
Whole exome sequencing is increasingly used in the diagnosis of primary immunodeficiencies due to the overlapping and atypical presentations of these disorders. We report two patients who presented with recurrent infections and early onset colitis. They were investigated by whole exome sequencing due to suspicion of primary immunodeficiency and found to have mutations in pyrin known to cause familial Mediterranean fever.