Research Article: Three novel compound heterozygous IL12RB1 mutations in Chinese patients with Mendelian susceptibility to mycobacterial disease

Date Published: April 18, 2019

Publisher: Public Library of Science

Author(s): Xiaopei Zhou, Weimin Jia, Zhengyi Ni, Ali Wang, Zhenxing Liu, Meiqi Hou, Mi Zhou, Zhongwen Tang, Dazhi Zhang, Lei Li, Tiantian Han, Yang Tan, Geng Luo, Jiarui Wang, Yanling Wu, Xianqin Zhang, Obul Reddy Bandapalli.


Mendelian Susceptibility to Mycobacterial Diseases (MSMD) is a primary immunodeficiency disease (PID) characterized by variable susceptibility to weakly virulent mycobacteria (Bacille Calmette-Guerin, BCG) and various intramacrophagic bacteria, fungi, parasites. Mycobacterial disease generally begins in childhood, more rarely during adolescence and adulthood. The pathogenesis of MSMD is the inherited impaired production of interferon gamma (IFN-γ) or inadequate response to it. Autosomal recessive IL12RB1 deficiency is the most common genetic etiology of MSMD. Here we identified three novel compound heterozygous mutations in IL12RB1 gene (c.635G>A, c.765delG; c.632G>C, c.847C>T; c.64G>A, c.1673insGAGCTTCCTGAG) in three Chinese families with MSMD.

Partial Text

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare inherited disease characterized by selective vulnerability to infections by weakly virulent mycobacteria (Bacillus Calmette-Guerin Vaccine, BCG) and other intramacrophagic bacteria (listeriosis, nocardiosis, klebsiellosis), fungi (candidiasis, histoplasmosis, paracoccidioidomycosis, coccidioidomycosis) and parasites (leishmaniasis, toxoplasmosis) [1]. MSMD mostly begins in childhood, and has various clinical manifestations, ranging from regional to disseminated infections with one or more mycobacterial species that may or may not recur [1]. The first disease gene of MSMD was identified in 1996, which was caused by bi-allelic null mutations of IFNGR1 [2]. Up to now, eleven MSMD-causing genes, including nine autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, IRF8, RORC and TYK2 and two X-linked (NEMO, and CYBB) genes have been identified [1, 3, 4]. IFN-γ is important for killing and controlling mycobacterial infections [5–6]. Most of these MSMD-disease genes mutations lead to either insufficient production of IFN-gamma (γ) or inadequate response to it [7].

BCG vaccine is the most commonly used to newborns. It is considered to be safe, but some complications have been reported like cellulitis, abscesses at the site of inoculation, regional lymphadenitis (BCGitis) and disseminated BCG infection (BCG-osis) [11]. Futhermore, the vast majority of the patients with complications reported with MSMD. The infections with the live attenuated Mycobacterium bovis Bacille Calmette-Guerin strain (BCG) of the tuberculosis (TB) vaccine, usually occurred only once in these patients [12].




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