Shahram Nemati1, Shahram Teimourian2, Mina Tabrizi3, Mehri Najafi4, Naghi Dara5, Farid Imanzadeh5, Mitra Ahmadi6, Maryam Kazemi Aghdam7, Mohmoud Tavassoli8, Pejman Rohani5, Seyyed Ramin Madani9, Martin de Boer10, T W Kuijpers10, Dirk Roos10. 1. Department of Medical Genetics, Tehran University of Medical Sciences, International Campus (TUMS-IC), Tehran, Iran. 2. Department of Medical Genetics, Iran University of Medical Sciences, Tehran, Iran; Pediatric Infectious Diseases Research Center, Department of Infectious Diseases, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: teimourian.sh@iums.ac.ir. 3. Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. 4. Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. 5. Department of Pediatric Gastroenterology, Hepatology and Nutrition, Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 6. Department of Pediatric Gastroenterology, Jondishapoor University of Medical Sciences, Ahvaz, Iran. 7. Shahid Beheshti University of Medical Sciences, Tehran, Iran. 8. Department of Allergy and Clinical Immunology, Isfahan University of Medical Sciences, Isfahan, Iran. 9. Department of Pediatric Gastroenterology, Kashan University of Medical Sciences, Kashan, Iran. 10. Sanquin Blood Supply Organization, and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
Abstract
BACKGROUND & AIM: Comparing to adult inflammatory bowel disease (IBD), those with early onset manifestations have different features in terms of the underlying molecular pathology, the course of disease and the response to therapy. We investigated the IL-10 signaling pathway previously reported as an important cause of infantile (Very Early Onset) IBD to find any possible variants. METHOD: With the next generation sequencing technique we screened IL-10, IL-10RA and IL10RB genes of 15 children affected by very early onset-GI (gastrointestinal) disorders. Additionally, we analyzed them based on Thermo Fisher immune deficiency panel for genes either having a known role in IBD pathogenesis or cause the disorders with overlapping manifestations. We performed multiple functional analyses only for the cases showing variants in IL-10- related genes. RESULT: In 3 out of 15 patients we identified variants including a homozygous and heterozygote mutations in IL-10RA and a novel homozygous mutation in IL-12RB1. Our functional studies reveal that in contrast to the IL-10RA heterozygote mutation that does not have deleterious effects, the homozygous mutation abrogates the IL-10 signaling pathway. CONCLUSION: Our study suggests we need to modify the classical diagnostic approach from functional assays followed by candidate- gene or genes sequencing to the firstly parallel genomic screening followed by functional studies.
BACKGROUND & AIM: Comparing to adult inflammatory bowel disease (IBD), those with early onset manifestations have different features in terms of the underlying molecular pathology, the course of disease and the response to therapy. We investigated the IL-10 signaling pathway previously reported as an important cause of infantile (Very Early Onset) IBD to find any possible variants. METHOD: With the next generation sequencing technique we screened IL-10, IL-10RA and IL10RB genes of 15 children affected by very early onset-GI (gastrointestinal) disorders. Additionally, we analyzed them based on Thermo Fisher immune deficiency panel for genes either having a known role in IBD pathogenesis or cause the disorders with overlapping manifestations. We performed multiple functional analyses only for the cases showing variants in IL-10- related genes. RESULT: In 3 out of 15 patients we identified variants including a homozygous and heterozygote mutations in IL-10RA and a novel homozygous mutation in IL-12RB1. Our functional studies reveal that in contrast to the IL-10RA heterozygote mutation that does not have deleterious effects, the homozygous mutation abrogates the IL-10 signaling pathway. CONCLUSION: Our study suggests we need to modify the classical diagnostic approach from functional assays followed by candidate- gene or genes sequencing to the firstly parallel genomic screening followed by functional studies.