Abstract
Recently, we have demonstrated that PRSS1 mutations cause ectopic trypsinogen activation and thereby result in type 1 autoimmune pancreatitis (AIP). However, the molecules involved in inducing obliterative vasculitis and perineural inflammation in the pancreas are not well-described. The present study applied whole-exome sequencing (WES) to determine the underlying etiology and revealed novel missense splice region variants, CALCB c.88T>C (p.Ser30Pro) and IR [1]-mutants, in 2 of the 3 families and 2 of 26 unrelated patients with type 1 AIP. In vitro, both of the mutants displayed decreased βCGRP, ERK1/2 phosphorylation, and co-localized with endoplasmic reticulum and Golgi apparatus. The novel pathogenic variant identified in this case should contribute to our understanding of the expanding spectrum of AIP.
Highlights
Type 1 autoimmune pancreatitis (AIP) is the pancreatic manifestation of a systemic fibroinflammatory IgG4-related disease
We considered the splice region variants detected in calcitonin generelated peptide beta (CALCB) as the disease-causing mutation in AIP1 and AIP2 families (Figure 1b)
The candidate pathogenic variants shared by the proband and his parents in AIP family were validated; these were potentially present in most of the affected males, or were absent in their male family members as controls and had not been previously reported or if it had a prevalence below 0.1% in the 1000 Genomes variant database
Summary
Type 1 autoimmune pancreatitis (AIP) is the pancreatic manifestation of a systemic fibroinflammatory IgG4-related disease. Mutations in protease serine 1 (PRSS1) (OMIM 276000), cystic fibrosis transmembrane conductance regulator (CFTR) (OMIM 602421), and pancreatic secretory trypsin inhibitor (SPINK1) (OMIM 167790) were causally linked to the pathogenesis of chronic pancreatitis.[4,5] Recently, we have reported PRSS1_IVS 2+56_60 delCCCAG and PRSS1_p.Leu81Met cause ectopic trypsinogen activation resulting in AIP.[6,7] we have observed the perineural inflammation and anti-collagen type IV antibodies co-localized with subepithelial IgG4 deposits along the capillary walls and surrounding nerve fibers in almost all patients,[8] which highlights the involvement of neural factors in the formation of autoimmune pancreatitis. The best-known function of CGRP is its effect on the peripheral vasculature It acts on the smooth muscle cells and causes vasodilatation via a non-endothelial mechanism through the activation of adenylate cyclase.[15] The release of perivascular peptides relaxes cerebral arteries concomitant with the stimulation of cyclic AMP (cAMP) accumulation or release of an endothelium-derived relaxing factor. We try to reveal the role of the CALCB mutations in development of obliterative vasculitis and perineural inflammation and the underlying mechanism(s)
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