Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease

ABSTRACT: Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare syndrome, the known genetic etiologies of which impair the production of, or the response to interferon-gamma (IFN-γ). We report here a patient (P1) with MSMD whose cells display mildly impaired responses to IFN-γ, at levels, however, similar to those from MSMD patients with autosomal recessive (AR) partial IFN-γR2 or STAT1 deficiency. Whole-exome sequencing (WES) and Sanger sequencing revealed only one candidate variation for both MSMD-causing and IFN-γ-related genes. P1 carried a heterozygous frame-shift IFNGR2 mutation inherited from her father. We show that the mutant allele is intrinsically loss-of-function and not dominant-negative, suggesting haploinsufficiency at the IFNGR2 locus. We also show that Epstein-Barr virus transformed B lymphocyte cells from 10 heterozygous relatives of patients with AR complete IFN-γR2 deficiency respond poorly to IFN-γ, in some cases as poorly as the cells of P1. Naive CD4(+) T cells and memory IL-4-producing T cells from these individuals also responded poorly to IFN-γ, whereas monocytes and monocyte-derived macrophages (MDMs) did not. This is consistent with the lower levels of expression of IFN-γR2 in lymphoid than in myeloid cells. Overall, MSMD in this patient is probably due to autosomal dominant (AD) IFN-γR2 deficiency, resulting from haploinsufficiency, at least in lymphoid cells. The clinical penetrance of AD IFN-γR2 deficiency is incomplete, possibly due, at least partly, to the variability of cellular responses to IFN-γ in these individuals.

• Autores: Moncada Vélez, Marcela; Kong, Xiao Fei; Vogt, Guillaume; Itan, Yuval; Macura Biegun, Anna; Szaflarska, Anna; Kowalczyk, Danuta; Chapgier, Ariane; Abhyankar, Avinash; Furthner, Dieter; Djambas Khayat, Claudia; Okada, Satoshi; Bryant, Vanessa L.; Bogunovic, Dusan; Kreins, Alexandra; Migaud, Melanie; Al-Ajaji, Sulaiman; Al-Muhsen, Saleh; Holland, Steven M.; Abel, Laurent; Picard, Capucine; Chaussabel, Damien; Bustamante, Jacinta; Casanova, Jean-Laurent; Boisson Dupuis, Stephanie
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2012
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/43120
• Acceso en línea: https://hdl.handle.net/10495/43120
• Palabra clave: B-Lymphocytes; Linfocitos B; Base Sequence; Secuencia de Bases; Case-Control Studies; Estudios de Casos y Controles; Cells, Cultured; Células Cultivadas; Gene Expression; Expresión Génica; Genes, Dominant; Genes Dominantes; Genetic Association Studies; Estudios de Asociación Genética; Genetic Predisposition to Disease; Predisposición Genética a la Enfermedad; Haploinsufficiency; HaploinsufIciencia; Heterozygote; Heterocigoto; Interferon-gamma; Interferón gamma; Mycobacterium Infections; Infecciones por Mycobacterium; Mycobacterium Infections, Nontuberculous; Infecciones por Mycobacterium no Tuberculosas; Oligonucleotide Array Sequence Analysis; Análisis de Secuencia por Matrices de Oligonucleótidos; Phosphorylation; Fosforilación; Protein Processing, Post-Translational; Procesamiento Proteico-Postraduccional; Receptors, Interferon; Receptores de Interferón; Sequence Analysis, DNA; Análisis de Secuencia de ADN; Sequence Deletion; Eliminación de Secuencia; https://id.nlm.nih.gov/mesh/D001402; https://id.nlm.nih.gov/mesh/D001483; https://id.nlm.nih.gov/mesh/D016022; https://id.nlm.nih.gov/mesh/D002478; https://id.nlm.nih.gov/mesh/D015870; https://id.nlm.nih.gov/mesh/D005799; https://id.nlm.nih.gov/mesh/D056726; https://id.nlm.nih.gov/mesh/D020022; https://id.nlm.nih.gov/mesh/D057895; https://id.nlm.nih.gov/mesh/D006579; https://id.nlm.nih.gov/mesh/D007371; https://id.nlm.nih.gov/mesh/D009164; https://id.nlm.nih.gov/mesh/D009165; https://id.nlm.nih.gov/mesh/D020411; https://id.nlm.nih.gov/mesh/D010766; https://id.nlm.nih.gov/mesh/D011499; https://id.nlm.nih.gov/mesh/D017471; https://id.nlm.nih.gov/mesh/D017422; https://id.nlm.nih.gov/mesh/D017384
• Rights: openAccess
• License: https://creativecommons.org/licenses/by-nc/4.0/