CALCB splice region pathogenic variants leading to plasma cell neurotropic enrichment in type 1 autoimmune pancreatitis

• Published in: Cell death & disease Vol. 8; no. 2; p. e2591
• Main Authors: Liu, Qi-cai, Chen, Falin, Wu, Chao-yang, Gao, Feng, Zhuang, Ze-hao, Chen, Jin-tong, Cai, Bin, Zhang, Tianming, Guo, Ling, Lin, Li-qing, Zhao, Cheng-fei, Lin, Xin-hua
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.02.2017; Springer Nature B.V; Nature Publishing Group
• Subjects: 38/23; 38/44; 38/91; 631/208/726/649; 631/208/737; 692/4020/1503/1712/1714/2755; 692/420/2489; Antibodies; Autoimmune Diseases - genetics; Autoimmune Diseases - pathology; Biochemistry; Biomedical and Life Sciences; Calcitonin Gene-Related Peptide - genetics; Cell Biology; Cell Culture; Cell Line; Endoplasmic Reticulum - genetics; Female; Golgi Apparatus - genetics; HEK293 Cells; Humans; Immunology; Inflammation - genetics; Inflammation - pathology; Life Sciences; Male; MAP Kinase Signaling System - genetics; Mutation; Mutation - genetics; Original; original-article; Pancreas; Pancreas - pathology; Pancreatitis - genetics; Pancreatitis - pathology; Pathogens; Phosphorylation - genetics; Plasma; Plasma Cells - pathology; Trypsin - genetics
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2017.32

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.