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Genomics of Gastrointestinal Disorders: a Familial Based Approach
Author(s) -
Coble Joel L.,
Sheldon Kathryn,
Yue Feng,
Schneper Lisa,
Choi Christine,
Poirier Kendra,
Salameh Tarik,
Harris Leonard,
Deiling Sue,
Ruggiero Francesca,
Broach James R.,
Koltun Walter A.,
Gerhard Glenn S.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.832.1
Subject(s) - missense mutation , exome sequencing , biology , genetics , pathogenesis , disease , single nucleotide polymorphism , inflammatory bowel disease , exome , gene , phenotype , pathology , medicine , immunology , genotype
Background Inflammatory Bowel Disease (IBD) and Diverticular Disease (DD) are both gastrointestinal disorders known to have a genetic component. IBD comprises both Ulcerative Colitis (UC) and Crohn's Disease (CD). The role of genetics is suggested to be 40–53% for DD and 75% for CD. However, less than 20% of the heritability of CD is accounted for by the known genomic loci. No causative genes have yet been implicated for DD. The purpose of our study is to identify novel genetic contributors to these diseases. Methods Using exome sequencing and 2 DD and 1 CD affected families with strong phenotypes, we identified missense single nucleotide variants (SNVs) whose segregation matched disease presentation in the families. The SNVs lie within genes that therefore may contribute to the pathogenesis of each disease. Targeted sequencing of those genes in non‐familial but affected (sporadic) patients was performed to identify any patients with other SNVs in those genes that also have disease. To assess the functional effect of these SNVs, immunofluorescence was performed to identify changes in protein localization and abundance. Results We found two rare missense variants in the genes for basement membrane proteins, LAMB4 and COL1A1, which each segregated with disease in separate DD affected families. Decreased expression of LAMB4 was observed in the myenteric plexus of patients with DD and variants in LAMB4 . This decreased expression may affect the development of the enteric nervous system, which can contribute to the pathogenesis of DD. We observed increased COL1A1 protein in the submucosa of patients with DD and with variants in COL1A1 . This increased expression confirms the increased collagen expression observed in DD. Altered plasticity of the submucosa may contribute to the development of DD. We identified multiple missense SNVs that matched the pattern of inheritance of the CD affected family and collectively may contribute to the development of CD. These include NOD2 interacting protein DDX58, a regulator of autophagy ATG4B, and a member of a protein family previously associated with CD, ADAMTS16. Conclusion We have identified additional SNVs and genes that may account for some of the missing heritability in CD. Additionally, we have identified the first genes to be associated with DD, LAMB4 and COL1A1 . Further research is needed to elucidate the genomic and molecular pathogenesis of these diseases.