title: Complex interaction between HNRNPD mutations and risk polymorphisms is associated with discordant Crohn's disease in monozygotic twins.
abstract: Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) affecting the lining of digestive tracts of the colon and ileum. To investigate the reasons behind the presence of CD phenotype in one of the monozygotic (MZ) twins, we utilized the whole exome sequence (WES) datasets of CD tissue biopsy and CD blood of affected twin and the exome dataset of blood from healthy twin. We report the presence of discordant and rare damaging mutation in HNRNPD and other risk polymorphisms such as, rs12103, rs2241880, rs3810936, rs7076156, rs1042058 and rs1292053. HNRNPD was found carrying two novel heterozygous mutations - a stop gain mutation that truncated the protein at 249th and 268th amino acid position and a single base missense mutation replacing Aspartate with Valine at 300th amino acid. The identified risk polymorphisms were found conferring susceptibility to CD and IBD. Discordant deleterious and damaging mutation was detected in HNRNPD that have been implicated in inflammatory pathways. Integrating these variants led to the elucidation of pathophysiology of CD in the affected twin involving the causal processes of macrophage activation, tissue death, autophagy, immune response, cell-migration and T-cell activation.
authors.affiliation: a Genetics and Genomics Lab, Department of Studies in Genetics and Genomics , University of Mysore , Mysuru , India.
authors.forename: Tejaswini
authors.initials: T
authors.lastname: Prakash
authors.affiliation: b Laboratory of Genomic Sciences, Department of Studies in Genetics and Genomics , University of Mysore , Mysuru , India.
authors.forename: Avinash
authors.initials: A
authors.lastname: Veerappa
authors.affiliation: a Genetics and Genomics Lab, Department of Studies in Genetics and Genomics , University of Mysore , Mysuru , India.
authors.forename: Nallur
authors.initials: N
authors.lastname: B Ramachandra
mesh_terms: D000483:Alleles; D003424:Crohn Disease / Q000235:genetics*; D004843:Epistasis, Genetic; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D014430:Twins, Monozygotic / Q000235:genetics*
chemical_list: D034502:Heterogeneous-Nuclear Ribonucleoprotein D
keywords: Crohn's disease; HNRNPD; MZ twins; autoimmunity; inflammation