Original Research ARTICLE
A Novel Splice Site Mutation in IFNGR2 in Patients with Primary Immunodeficiency Exhibiting Susceptibility to Mycobacterial Diseases
- 1National Institute of Mental Health and Neurosciences, India
- 2Department of Laboratory Medicine and Pathology, Mayo Clinic, United States
- 3Center for Individualized Medicine, Mayo Clinic, United States
- 4Institute of Bioinformatics (IOB), India
- 5Manipal Academy of Higher Education, India
- 6Florey Institute of Neuroscience and Mental Health, Australia
- 7Mazumdar Shaw Medical Centre, India
- 8Neuromuscular Laboratory, Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), India
- 9National Institute of Immunohaematology (ICMR), India
Primary immunodeficiency (PID) refers to a group of heterogeneous genetic disorders with a weakened immune system. Mendelian susceptibility to mycobacterial disease (MSMD) is a subset of PID in which patients exhibit defects in intrinsic and innate immunity. It is a rare congenital disorder characterized by severe and recurrent infections caused by weakly virulent mycobacteria or other environmental mycobacteria. Any delay in definitive diagnosis poses a major concern due to the confounding nature of infections and immune deficiencies. Here, we report the clinical, immunological and genetic characteristics of two siblings (infants) with recurrent infections. There was a history of death of two other siblings in the family after BCG vaccination. Whole exome sequencing of the two affected surviving infants along with their consanguineous parents identified a novel, homozygous single nucleotide splice acceptor site variant in intron 2 of the interferon gamma receptor 2 (IFNGR2) gene. Sanger sequencing of DNA obtained from blood and fibroblasts confirmed the variant. The patients underwent bone marrow transplantation from their father as a donor. RT-PCR and Sanger sequencing of the cDNA of patients from blood samples after transplantation showed the expression of both wild type and mutant transcript expression of IFNGR2. To assess partial or complete expression of IFNGR2 transcripts, fibroblasts were cultured from skin biopsies. RT-PCR and Sanger sequencing of cDNA obtained from patient fibroblasts revealed complete expression of mutant allele and acquisition of a cryptic splice acceptor site in exon 3 that resulted in deletion of nine nucleotides in exon 3. This led to an in-frame deletion of three amino acids p.(Thr70-Ser72) located in a fibronectin type III (FN3) domain in the extracellular region of IFNGR2. This illustrates individualized medicine enabled by next generation sequencing as identification of this mutation helped in the clinical diagnosis of MSMD in the infants as well as in choosing the most appropriate therapeutic option.
Keywords: IFNGR2 deficiency, Gene Therapy, IFN gamma signaling, Non-tuberculous mycobacteria, immunodeficiency, Infection
Received: 13 Mar 2019;
Accepted: 05 Aug 2019.
Edited by:Antonio Condino-Neto, University of São Paulo, Brazil
Reviewed by:Asghar Aghamohammadi, Tehran University of Medical Sciences, Iran
Jacinta Bustamante, Université Paris Descartes, France
Copyright: © 2019 Pandey, Bandari, Muthusamy, Bhat, Govindaraj, Rajagopalan, Dalvi, Shankar, Raja, Reddy and Madkaikar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Prof. Akhilesh Pandey, National Institute of Mental Health and Neurosciences, Bangalore, 560029, Karnataka, India, firstname.lastname@example.org
Dr. Sunil Bhat, Mazumdar Shaw Medical Centre, Bengaluru, Karnataka, India, email@example.com
Dr. Manisha R. Madkaikar, National Institute of Immunohaematology (ICMR), Mumbai, Maharashtra, India, firstname.lastname@example.org