Article Text

other Versions

PDF
Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk
  1. Sebastian Beer1,
  2. Jiayi Zhou1,
  3. András Szabó1,
  4. Steven Keiles2,
  5. Giriraj Ratan Chandak3,
  6. Heiko Witt4,5,
  7. Miklós Sahin-Tóth1
  1. 1Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston University, Boston, Massachusetts, USA
  2. 2Ambry Genetics Corp., Aliso Viejo, California, USA
  3. 3Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research, Hyderabad, India
  4. 4Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ) & Zentralinstitut für Ernährungs- und Lebensmittelforschung (ZIEL), Technische Universität München (TUM), Freising, Germany
  5. 5Department of Pediatrics, Klinikum rechts der Isar (MRI), Technische Universität München (TUM), Munich, Germany
  1. Correspondence to Dr Miklós Sahin-Tóth, Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston University, 72 East Concord Street, Evans-433, Boston, MA 02118, USA; miklos{at}bu.edu

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.

  • Pancreatitis
  • Pancreatic Disease
  • Pancreatic Physiology
  • Pancreatic Disorders
  • Pancreatic Enzymes

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.