Elastase 3B mutation links to familial pancreatitis with diabetes and pancreatic adenocarcinoma

Abstract

Authorship note: PCM and JTC are co-first authors. Conflict of interest: MSG holds stock in Viacyte Inc. and Encellin Inc. MA holds stock in Medtronic and Merck. SAO is a scientific co-founder of, equity holder in, and consultant for OptiKira LLC.

The reversion variant (p.Arg90Leu) at the evolutionarily adaptive p.Arg90 site in CELA3B predisposes to chronic pancreatitis

“…This is consistent with two observations. First, the previously reported CP-causing p.Arg90Cys is a gain-of-function variant by virtue of its upregulatory effect on translation 20 . Second, the pLI score for CELA3B in genomAD (http://gnomad.broadinstitute.org/; as of 13 November 2020) is 0, suggesting that the gene is completely tolerant of heterozygous loss-of-function variants.…”

“…p.Arg90Leu is also absent from the 574 French subjects in the public dataset of the French Exome (FrEx) project 33 and is extremely rare in gnomAD (allele frequency 0.0008097 in all populations). Most importantly, this variant has been previously subjected to functional characterization together with the disease-causing CELA3B p.Arg90Cys variant; these variants were remarkably similar in terms of all their measured biochemical and functional parameters as well as mouse phenotypes 20 . It should be noted that the p.Arg90Leu variant had not been found in any patient in the original Moore study; it was functionally analyzed because, of the six human elastases, only CELA3B has an arginine at position 90 whereas all the others have a leucine 20 .…”

“…Most importantly, this variant has been previously subjected to functional characterization together with the disease-causing CELA3B p.Arg90Cys variant; these variants were remarkably similar in terms of all their measured biochemical and functional parameters as well as mouse phenotypes 20 . It should be noted that the p.Arg90Leu variant had not been found in any patient in the original Moore study; it was functionally analyzed because, of the six human elastases, only CELA3B has an arginine at position 90 whereas all the others have a leucine 20 . In this regard, we constructed the phylogenetic tree of the human elastase paralogues by means of NGPhylogeny.fr 34 , thereby formally confirming that p.Leu90 represents the ancestral allele whereas p.Arg90 is the derived allele ( Figure 1B).…”

“…In this regard, we constructed the phylogenetic tree of the human elastase paralogues by means of NGPhylogeny.fr 34 , thereby formally confirming that p.Leu90 represents the ancestral allele whereas p.Arg90 is the derived allele ( Figure 1B). Interestingly, replacement of p.Leu90 of the human wild-type CELA3A by arginine was found to reduce protein expression 20 . The constellation of these genetic, functional and evolutionary data therefore argues that p.Arg90 in CELA3B was an evolutionarily adaptive change and that reversion to the ancestral allele predisposes to CP.…”

Zelluläre Pathomechanismen der akuten Pankreatitis

“…So finden sich vermehrt Mutationen im kationischen Trypsinogen (PRSS1; [39]) sowie in Spink1 ("serine peptidase inhibitor, Kazal type 1"; [40]), einem Inhibitor für Trypsin. Weiterhin konnten aber auch Mutationen im Chymotrypsin C [19], der Carboxypeptidase A1 (CPA1; [41]) und der pankreatischen Elastase [42] gefunden werden. Jedoch konnte bis heute nicht der vollständige pathophysiologische Mechanismus hinter den einzelnen Mutationen aufgedeckt werden.…”