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A 584 bp deletion in CTRB2 inhibits chymotrypsin B2 activity and secretion and confers risk of pancreatic cancer.

ABSTRACT: Genome-wide association studies (GWASs) have discovered 20 risk loci in the human genome where germline variants associate with risk of pancreatic ductal adenocarcinoma (PDAC) in populations of European ancestry. Here, we fine-mapped one such locus on chr16q23.1 (rs72802365, p = 2.51 × 10^-17, OR = 1.36, 95% CI = 1.31-1.40) and identified colocalization (PP = 0.87) with aberrant exon 5-7 CTRB2 splicing in pancreatic tissues (p_GTEx = 1.40 × 10^-69, β_GTEx = 1.99; p_LTG = 1.02 × 10^-30, β_LTG = 1.99). Imputation of a 584 bp structural variant overlapping exon 6 of CTRB2 into the GWAS datasets resulted in a highly significant association with pancreatic cancer risk (p = 2.83 × 10^-16, OR = 1.36, 95% CI = 1.31-1.42), indicating that it may underlie this signal. Exon skipping attributable to the deletion (risk) allele introduces a premature stop codon in exon 7 of CTRB2, yielding a truncated chymotrypsinogen B2 protein that lacks chymotrypsin activity, is poorly secreted, and accumulates intracellularly in the endoplasmic reticulum (ER). We propose that intracellular accumulation of a nonfunctional chymotrypsinogen B2 protein leads to ER stress and pancreatic inflammation, which may explain the increased pancreatic cancer risk in carriers of CTRB2 exon 6 deletion alleles.

SUBMITTER: Jermusyk A

PROVIDER: S-EPMC8546220 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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A 584 bp deletion in CTRB2 inhibits chymotrypsin B2 activity and secretion and confers risk of pancreatic cancer.

Jermusyk Ashley A Zhong Jun J Connelly Katelyn E KE Gordon Naomi N Perera Sumeth S Abdolalizadeh Ehssan E Zhang Tongwu T O'Brien Aidan A Hoskins Jason W JW Collins Irene I Eiser Daina D Yuan Chen C Risch Harvey A HA Jacobs Eric J EJ Li Donghui D Du Mengmeng M Stolzenberg-Solomon Rachael Z RZ Klein Alison P AP Smith Jill P JP Wolpin Brian M BM Chanock Stephen J SJ Shi Jianxin J Petersen Gloria M GM Westlake Christopher J CJ Amundadottir Laufey T LT

American journal of human genetics 20210923 10

Genome-wide association studies (GWASs) have discovered 20 risk loci in the human genome where germline variants associate with risk of pancreatic ductal adenocarcinoma (PDAC) in populations of European ancestry. Here, we fine-mapped one such locus on chr16q23.1 (rs72802365, p = 2.51 × 10-17, OR = 1.36, 95% CI = 1.31-1.40) and identified colocalization (PP = 0.87) with aberrant exon 5-7 CTRB2 splicing in pancreatic tissues (pGTEx = 1.40 × 10-69, βGTEx ...[more]

PMID: 34559995

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Project description:Even though all animal alpha-amylases include glycosylation sequons (Asn-Xaa-Thr/Ser) in their sequences, amylases purified from natural sources are not quantitatively glycosylated. When wild-type rat pancreatic alpha-amylase, which contains two glycosylation sequons, was expressed in animal cell lines the protein displayed a very low rate of glycosylation (approx. 2%), even after Brefeldin A treatment to increase the contact with the glycosylation machinery. Site-directed mutagenesis of the first glycosylation sequon (Asn(410)-->Gln) resulted in 90% of the protein being glycosylated at the second glycosylation sequon (Asn(459)). Mutation of the second sequon completely inhibited glycosylation. In order to ascertain if the interference in the glycosylation of Asn(459) that was eliminated by the Asn(410)-->Gln mutation could be due to the position of the asparagine residue in the Cys(448)-Cys(460) disulphide bridge, these cysteine residues were mutated to serine residues. The resulting mutant was found to be 100% glycosylated. All mutants with mutations in the C-domain had specific activities identical to that of the wild-type enzyme, indicating that enzymic activity is independent of the structure and modification of the C-terminal domain. To further test the independence of the C-domain with respect to the two N-terminal domains of the protein, which harbour the catalytic site, the last seven of the ten beta\beta-strands that make up the beta-sandwich configuration of the domain were deleted. The truncated protein was not secreted from cells and all enzyme activity was destroyed. These observations show that Asn(459) is the only site that can be glycosylated in wild-type amylase, and confirm the relative independence of the C-terminal domain of alpha-amylase with respect to enzyme activity. In addition, they also establish that the C-terminal domain is absolutely essential for the correct post-translational folding of the enzyme that is responsible for its activity and allows for its secretion.

Dataset Information

A 584 bp deletion in CTRB2 inhibits chymotrypsin B2 activity and secretion and confers risk of pancreatic cancer.

Publications

A 584 bp deletion in CTRB2 inhibits chymotrypsin B2 activity and secretion and confers risk of pancreatic cancer.

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