Rare variant burden analysis from exomes of three consanguineous families reveals LILRB1 and PRSS3 as potential key proteins in inflammatory bowel disease pathogenesis
BackgroundInflammatory bowel disease (IBD) is a chronic autoimmune disorder characterized by severe inflammation and mucosal destruction of the intestine. The specific, complex molecular processes underlying IBD pathogenesis are not well understood. Therefore, this study is aimed at identifying and...
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Frontiers Media S.A.
2023-05-01
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| Series: | Frontiers in Medicine |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmed.2023.1164305/full |
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| author | Rana Mohammed Jan Rana Mohammed Jan Huda Husain Al-Numan Huda Husain Al-Numan Nada Hassan Al-Twaty Nuha Alrayes Nuha Alrayes Hadeel A. Alsufyani Meshari A. Alaifan Bakr H. Alhussaini Noor Ahmad Shaik Noor Ahmad Shaik Zuhier Awan Yousef Qari Omar I. Saadah Omar I. Saadah Babajan Banaganapalli Babajan Banaganapalli Mahmoud Hisham Mosli Mahmoud Hisham Mosli Ramu Elango Ramu Elango |
| author_facet | Rana Mohammed Jan Rana Mohammed Jan Huda Husain Al-Numan Huda Husain Al-Numan Nada Hassan Al-Twaty Nuha Alrayes Nuha Alrayes Hadeel A. Alsufyani Meshari A. Alaifan Bakr H. Alhussaini Noor Ahmad Shaik Noor Ahmad Shaik Zuhier Awan Yousef Qari Omar I. Saadah Omar I. Saadah Babajan Banaganapalli Babajan Banaganapalli Mahmoud Hisham Mosli Mahmoud Hisham Mosli Ramu Elango Ramu Elango |
| author_sort | Rana Mohammed Jan |
| collection | DOAJ |
| description | BackgroundInflammatory bowel disease (IBD) is a chronic autoimmune disorder characterized by severe inflammation and mucosal destruction of the intestine. The specific, complex molecular processes underlying IBD pathogenesis are not well understood. Therefore, this study is aimed at identifying and uncovering the role of key genetic factors in IBD.MethodThe whole exome sequences (WESs) of three consanguineous Saudi families having many siblings with IBD were analyzed to discover the causal genetic defect. Then, we used a combination of artificial intelligence approaches, such as functional enrichment analysis using immune pathways and a set of computational functional validation tools for gene expression, immune cell expression analyses, phenotype aggregation, and the system biology of innate immunity, to highlight potential IBD genes that play an important role in its pathobiology.ResultsOur findings have shown a causal group of extremely rare variants in the LILRB1 (Q53L, Y99N, W351G, D365A, and Q376H) and PRSS3 (F4L and V25I) genes in IBD-affected siblings. Findings from amino acids in conserved domains, tertiary-level structural deviations, and stability analysis have confirmed that these variants have a negative impact on structural features in the corresponding proteins. Intensive computational structural analysis shows that both genes have very high expression in the gastrointestinal tract and immune organs and are involved in a variety of innate immune system pathways. Since the innate immune system detects microbial infections, any defect in this system could lead to immune functional impairment contributing to IBD.ConclusionThe present study proposes a novel strategy for unraveling the complex genetic architecture of IBD by integrating WES data of familial cases, with computational analysis. |
| first_indexed | 2024-04-09T14:19:06Z |
| format | Article |
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| language | English |
| last_indexed | 2024-04-09T14:19:06Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Medicine |
| spelling | doaj.art-fba547d57ef14394b5c1d488e81569bd2023-05-05T05:48:54ZengFrontiers Media S.A.Frontiers in Medicine2296-858X2023-05-011010.3389/fmed.2023.11643051164305Rare variant burden analysis from exomes of three consanguineous families reveals LILRB1 and PRSS3 as potential key proteins in inflammatory bowel disease pathogenesisRana Mohammed Jan0Rana Mohammed Jan1Huda Husain Al-Numan2Huda Husain Al-Numan3Nada Hassan Al-Twaty4Nuha Alrayes5Nuha Alrayes6Hadeel A. Alsufyani7Meshari A. Alaifan8Bakr H. Alhussaini9Noor Ahmad Shaik10Noor Ahmad Shaik11Zuhier Awan12Yousef Qari13Omar I. Saadah14Omar I. Saadah15Babajan Banaganapalli16Babajan Banaganapalli17Mahmoud Hisham Mosli18Mahmoud Hisham Mosli19Ramu Elango20Ramu Elango21Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi ArabiaPrincess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi ArabiaDepartment of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi ArabiaPrincess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi ArabiaDepartment of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi ArabiaPrincess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi ArabiaDepartment of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi ArabiaDepartment of Medical Physiology, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi ArabiaDepartment of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi ArabiaDepartment of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi ArabiaPrincess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi ArabiaDepartment of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi ArabiaDepartment of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi ArabiaDepartment of Internal Medicine, King Abdulaziz University, Jeddah, Saudi ArabiaDepartment of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi ArabiaInflammatory Bowel Disease Research Group, King Abdulaziz University, Jeddah, Saudi ArabiaPrincess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi ArabiaDepartment of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi ArabiaDepartment of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi ArabiaInflammatory Bowel Disease Research Group, King Abdulaziz University, Jeddah, Saudi ArabiaPrincess Al-Jawhara Al-Brahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi ArabiaDepartment of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi ArabiaBackgroundInflammatory bowel disease (IBD) is a chronic autoimmune disorder characterized by severe inflammation and mucosal destruction of the intestine. The specific, complex molecular processes underlying IBD pathogenesis are not well understood. Therefore, this study is aimed at identifying and uncovering the role of key genetic factors in IBD.MethodThe whole exome sequences (WESs) of three consanguineous Saudi families having many siblings with IBD were analyzed to discover the causal genetic defect. Then, we used a combination of artificial intelligence approaches, such as functional enrichment analysis using immune pathways and a set of computational functional validation tools for gene expression, immune cell expression analyses, phenotype aggregation, and the system biology of innate immunity, to highlight potential IBD genes that play an important role in its pathobiology.ResultsOur findings have shown a causal group of extremely rare variants in the LILRB1 (Q53L, Y99N, W351G, D365A, and Q376H) and PRSS3 (F4L and V25I) genes in IBD-affected siblings. Findings from amino acids in conserved domains, tertiary-level structural deviations, and stability analysis have confirmed that these variants have a negative impact on structural features in the corresponding proteins. Intensive computational structural analysis shows that both genes have very high expression in the gastrointestinal tract and immune organs and are involved in a variety of innate immune system pathways. Since the innate immune system detects microbial infections, any defect in this system could lead to immune functional impairment contributing to IBD.ConclusionThe present study proposes a novel strategy for unraveling the complex genetic architecture of IBD by integrating WES data of familial cases, with computational analysis.https://www.frontiersin.org/articles/10.3389/fmed.2023.1164305/fullinflammatory bowel diseasemissense mutationCrohn’s diseasegastrointestinal tractprotein modeling |
| spellingShingle | Rana Mohammed Jan Rana Mohammed Jan Huda Husain Al-Numan Huda Husain Al-Numan Nada Hassan Al-Twaty Nuha Alrayes Nuha Alrayes Hadeel A. Alsufyani Meshari A. Alaifan Bakr H. Alhussaini Noor Ahmad Shaik Noor Ahmad Shaik Zuhier Awan Yousef Qari Omar I. Saadah Omar I. Saadah Babajan Banaganapalli Babajan Banaganapalli Mahmoud Hisham Mosli Mahmoud Hisham Mosli Ramu Elango Ramu Elango Rare variant burden analysis from exomes of three consanguineous families reveals LILRB1 and PRSS3 as potential key proteins in inflammatory bowel disease pathogenesis Frontiers in Medicine inflammatory bowel disease missense mutation Crohn’s disease gastrointestinal tract protein modeling |
| title | Rare variant burden analysis from exomes of three consanguineous families reveals LILRB1 and PRSS3 as potential key proteins in inflammatory bowel disease pathogenesis |
| title_full | Rare variant burden analysis from exomes of three consanguineous families reveals LILRB1 and PRSS3 as potential key proteins in inflammatory bowel disease pathogenesis |
| title_fullStr | Rare variant burden analysis from exomes of three consanguineous families reveals LILRB1 and PRSS3 as potential key proteins in inflammatory bowel disease pathogenesis |
| title_full_unstemmed | Rare variant burden analysis from exomes of three consanguineous families reveals LILRB1 and PRSS3 as potential key proteins in inflammatory bowel disease pathogenesis |
| title_short | Rare variant burden analysis from exomes of three consanguineous families reveals LILRB1 and PRSS3 as potential key proteins in inflammatory bowel disease pathogenesis |
| title_sort | rare variant burden analysis from exomes of three consanguineous families reveals lilrb1 and prss3 as potential key proteins in inflammatory bowel disease pathogenesis |
| topic | inflammatory bowel disease missense mutation Crohn’s disease gastrointestinal tract protein modeling |
| url | https://www.frontiersin.org/articles/10.3389/fmed.2023.1164305/full |
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