Inherited p40phox deficiency differs from classic chronic granulomatous disease

ABSTRACT: Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.

• Autores: Cabarcas Jaramillo, Felipe; Alzate Restrepo, Juan Fernando; Arango Franco, Carlos Andrés; Franco Restrepo, José Luis; Moncada Vélez, Marcela; Arias Sierra, Andrés Augusto; Garcés Samudio, Carlos Guillermo
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2018
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/33274
• Acceso en línea: https://hdl.handle.net/10495/33274
• Palabra clave: Técnicas de Inactivación de Genes; Gene Knockout Techniques; Enfermedad Granulomatosa Crónica; Granulomatous Disease, Chronic; Células HEK293; HEK293 Cells; Mutación con Pérdida de Función; Loss of Function Mutation; Proteínas Mutantes; Mutant Proteins; NADPH Oxidasas; NADPH Oxidases; Fagocitos; Phagocytes; Fosfoproteínas; Phosphoproteins; ARN Mensajero; RNA, Messenger; Transducción Genética; Transduction, Genetic
• Rights: openAccess
• License: http://creativecommons.org/licenses/by-nc-sa/2.5/co/