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

Xiaopei Zhou,Zhongwen Tang,Ali Wang,Yanling Wu,Dazhi Zhang,Zhenxing Liu,Geng Luo,Tiantian Han,Meiqi Hou,Yang Tan,Zhengyi Ni,Jiarui Wang,Xianqin Zhang,Weimin Jia,Lei Li,Mi Zhou

doi:10.1371/journal.pone.0215648

Abstract

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.

Highlights

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, Bacille Calmette-Guerin strain (BCG)) and other intramacrophagic bacteria, fungi and parasites [1]
100 unrelated normal controls who received BCG vaccine and without Mendelian Susceptibility to Mycobacterial Diseases (MSMD) did not carry the two mutations, this mutation not reported in other database (1000 Genomes Project and NHLBI Exome Sequencing Project)
BCG vaccine is the most commonly used to newborns

Summary

Introduction

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]. 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]

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Results

Conclusion