Format

Send to

Choose Destination
See comment in PubMed Commons below
Gut. 2013 Nov;62(11):1616-24. doi: 10.1136/gutjnl-2012-303090. Epub 2012 Sep 1.

Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk.

Author information

1
Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston University, Boston, Massachusetts, USA.

Abstract

OBJECTIVE:

The digestive enzyme chymotrypsin C (CTRC) protects against pancreatitis by promoting degradation of trypsinogen, thereby curtailing potentially harmful trypsinogen activation. Loss-of-function variants in CTRC increase the risk for chronic pancreatitis. The aim of the present study was to perform comprehensive functional analysis of all missense CTRC variants identified to date.

DESIGN:

We investigated secretion, activity and degradation of 27 published and five novel CTRC mutants. We also assessed the effect of five mutants on endoplasmic reticulum (ER) stress.

RESULTS:

None of the mutants exhibited a gain of function, such as increased secretion or activity. By contrast, 11 mutants showed marked loss of function, three mutants had moderate functional defects, whereas 18 mutants were functionally similar to wild-type CTRC. The functional deficiencies observed were diminished secretion, impaired catalytic activity and degradation by trypsin. Mutants with a secretion defect caused ER stress that was proportional to the loss in secretion. ER stress was not associated with loss-of-function phenotypes related to catalytic defect or proteolytic instability.

CONCLUSIONS:

Pathogenic CTRC variants cause loss of function by three distinct but mutually non-exclusive mechanisms that affect secretion, activity and proteolytic stability. ER stress may be induced by a subset of CTRC mutants, but does not represent a common pathological mechanism of CTRC variants. This phenotypic dataset should aid in the classification of the clinical relevance of CTRC variants identified in patients with chronic pancreatitis.

KEYWORDS:

Pancreatic Disease; Pancreatic Disorders; Pancreatic Enzymes; Pancreatic Physiology; Pancreatitis

PMID:
22942235
PMCID:
PMC3660471
DOI:
10.1136/gutjnl-2012-303090
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center