Common single-base insertions in the VNTR of the carboxyl ester lipase (CEL) gene are benign and also likely to arise somatically in the exocrine pancreas

• Published in: Human molecular genetics 2024-05, Vol.33 (11), p.1001-1014
• Main Authors: Brekke, Ranveig S, Gravdal, Anny, El Jellas, Khadija, Curry, Grace E, Lin, Jianguo, Wilhelm, Steven J, Steine, Solrun J, Mas, Eric, Johansson, Stefan, Lowe, Mark E, Johansson, Bente B, Xiao, Xunjun, Fjeld, Karianne, Molven, Anders
• Format: Article
• Language: English
• Subjects: Alleles; Animals; Female; Gene Frequency; HEK293 Cells; Humans; Lipase - genetics; Male; Mice; Minisatellite Repeats - genetics; Mutagenesis, Insertional - genetics; Original; Pancreas, Exocrine - enzymology; Pancreas, Exocrine - metabolism; Pancreatic Neoplasms - enzymology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddae034

Abstract The CEL gene encodes carboxyl ester lipase, a pancreatic digestive enzyme. CEL is extremely polymorphic due to a variable number tandem repeat (VNTR) located in the last exon. Single-base deletions within this VNTR cause the inherited disorder MODY8, whereas little is known about VNTR single-base insertions in pancreatic disease. We therefore mapped CEL insertion variants (CEL-INS) in 200 Norwegian patients with pancreatic neoplastic disorders. Twenty-eight samples (14.0%) carried CEL-INS alleles. Most common were insertions in repeat 9 (9.5%), which always associated with a VNTR length of 13 repeats. The combined INS allele frequency (0.078) was similar to that observed in a control material of 416 subjects (0.075). We performed functional testing in HEK293T cells of a set of CEL-INS variants, in which the insertion site varied from the first to the 12th VNTR repeat. Lipase activity showed little difference among the variants. However, CEL-INS variants with insertions occurring in the most proximal repeats led to protein aggregation and endoplasmic reticulum stress, which upregulated the unfolded protein response. Moreover, by using a CEL-INS-specific antibody, we observed patchy signals in pancreatic tissue from humans without any CEL-INS variant in the germline. Similar pancreatic staining was seen in knock-in mice expressing the most common human CEL VNTR with 16 repeats. CEL-INS proteins may therefore be constantly produced from somatic events in the normal pancreatic parenchyma. This observation along with the high population frequency of CEL-INS alleles strongly suggests that these variants are benign, with a possible exception for insertions in VNTR repeats 1–4.