Missense splice variant (g.20746A>G, p.Ile183Val) of interferon gamma receptor 1 (IFNGR1) coincidental with mycobacterial osteomyelitis - a screen of osteoarticular lesions

Agnieszka Bińczak-Kuleta; Aleksander Szwed; Mark R. Walter; Maciej Kołban; Andrzej Ciechanowicz; Jeremy S. C. Clark

doi:10.17305/bjbms.2016.1232

Authors

Agnieszka Bińczak-Kuleta Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, Szczecin, Poland
Aleksander Szwed Department of Orthopedics and Child Traumatology, Pomeranian Medical University in Szczecin, Szczecin, Poland
Mark R. Walter Department of Microbiology, Bevill Biomedical Research Building, University of Alabama at Birmingham, Birmingham, AL, USA
Maciej Kołban Department of Orthopedics and Child Traumatology, Pomeranian Medical University in Szczecin, Szczecin, Poland
Andrzej Ciechanowicz Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, Szczecin, Poland
Jeremy S. C. Clark Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, Szczecin, Poland

DOI:

https://doi.org/10.17305/bjbms.2016.1232

Keywords:

Bacilli strain Calmette-Guerin, environmental mycobacteria, interferon gamma receptor 1, Mendelian susceptibility to mycobacterial disease, Mycobacterium bovis bacillus Calmette-Guérin, osteoarticular lesions

Abstract

Previously, dominant partial interferon-gamma receptor 1 (IFN-g-R1) susceptibility to environmental mycobacteria was found with IFNGR1 deletions or premature stop. Our aim was to search for IFNGR1 variants in patients with mycobacterial osteoarticular lesions. Biopsies from the patients were examined for acid-fast bacilli, inflammatory cell infiltration, and mycobacterial niacin. Mycobacterial rRNA was analyzed using a target-amplified rRNA probe test. Peripheral-blood-leukocyte genomic DNA was isolated from 19 patients using the QIAamp DNA Mini Kit, and all IFNGR1 exons were sequenced using an ABIPRISM 3130 device. After the discovery of an exon 5 variant, a Polish newborn population sample (n = 100) was assayed for the discovered variant. Splice sites and putative amino acid interactions were analyzed. All patients tested were positive for mycobacteria; one was heterozygous for the IFNGR1 exon 5 single-nucleotide-missense substitution (g.20746A>G, p.Ile183Val). No other variant was found. The splice analysis indicated the creation of an exonic splicing silencer, and alternatively, molecular graphics indicated that the p.Ile183Val might alter beta-strand packing (loss of van der Waals contacts; Val183/Pro205), possibly altering the IFN-g-R1/IFN-g-R2 interaction. The probability of non-deleterious variant was estimated as <10%. Heterozygous IFNGR1:p.Ile183Val (frequency 0.003%) was found to be coincidental with mycobacterial osteomyelitis. The small amount of variation detected in the patients with osteoarticular lesions indicates that screens should not yet be restricted: Intronic variants should be analyzed as well as the other genes affecting Type 1 T-helper-cell-mediated immunity.

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Author Biographies

Agnieszka Bińczak-Kuleta, Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, Szczecin, Poland

Department of Clinical and Molecular Biochemistry
Aleksander Szwed, Department of Orthopedics and Child Traumatology, Pomeranian Medical University in Szczecin, Szczecin, Poland

Department of Orthopedics and Child Traumatology
Mark R. Walter, Department of Microbiology, Bevill Biomedical Research Building, University of Alabama at Birmingham, Birmingham, AL, USA

Department of Microbiology
Maciej Kołban, Department of Orthopedics and Child Traumatology, Pomeranian Medical University in Szczecin, Szczecin, Poland

Department of Orthopedics and Child Traumatology
Andrzej Ciechanowicz, Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, Szczecin, Poland

Department of Clinical and Molecular Biochemistry
Jeremy S. C. Clark, Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, Szczecin, Poland

Department of Clinical and Molecular Biochemistry

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