Evidence map›Paper›PMID 38876922›Full record

ArticlePancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]2024

Novel chymotrypsin C (CTRC) variants from real-world genetic testing of pediatric chronic pancreatitis cases.

Regina Stefanovics, Máté Sándor, Alexandra Demcsák, Gergő Berke, Balázs Csaba Németh, Wenying Zhang, Maisam Abu-El-Haija, Miklós Sahin-Tóth

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.], 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

4 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
  4. Misfolding PRSS1 variant p.Ala61Val in a case of suspected intrauterine pancreatitis.Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] · 2025
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors.

Regina StefanovicsDepartment of Surgery, University of California Los Angeles, Los Angeles, CA, USA; Hungarian Centre of Excellence for Molecular Medicine - University of Szeged, Translational Pancreatology Research Group, Szeged, Hungary; Center for Gastroenterology, Department of Medicine, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary.
Máté SándorDepartment of Surgery, University of California Los Angeles, Los Angeles, CA, USA.
Alexandra DemcsákDepartment of Surgery, University of California Los Angeles, Los Angeles, CA, USA.
Gergő BerkeDepartment of Surgery, University of California Los Angeles, Los Angeles, CA, USA.
Balázs Csaba NémethHungarian Centre of Excellence for Molecular Medicine - University of Szeged, Translational Pancreatology Research Group, Szeged, Hungary; Center for Gastroenterology, Department of Medicine, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary.
Wenying ZhangDivision of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
Maisam Abu-El-HaijaDepartment of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Miklós Sahin-TóthDepartment of Surgery, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: msahintoth@mednet.ucla.edu.

Funding

Chymotrypsin in pancreatitisR01DK082412 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI SAHIN-TOTH, MIKLOS · 2009 to 2024
$5.8M
Trypsin-dependent mechanisms in pancreatitisR01DK117809 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI SAHIN-TOTH, MIKLOS · 2018 to 2022
$2.5M
NIDDK NIH HHS R01 DK082412NIDDK NIH HHS R01 DK117809
6 · The paper itself

Abstract

backgroundChymotrypsin C (CTRC) protects the pancreas against unwanted intrapancreatic trypsin activity through degradation of trypsinogen. Loss-of-function CTRC variants increase the risk for chronic pancreatitis (CP). The aim of the present study was to characterize novel CTRC variants found during genetic testing of CP cases at a pediatric pancreatitis center.

methodsWe used next-generation sequencing to screen patients. We analyzed the functional effects of CTRC variants in HEK 293T cells and using purified enzymes.

resultsIn 5 separate cases, we detected 5 novel heterozygous CTRC variants: c.407C>T (p.Thr136Ile), c.550G>A (p.Ala184Thr), c.627Cdup (p.Ser210Leufs∗?, where the naming indicates a frame shift with no stop codon), c.628T>C (p.Ser210Pro), and c.779A>G (p.Asp260Gly). Functional studies revealed that with the exception of p.Ser210Leufs∗?, the CTRC variants were secreted normally from transfected cells. Enzyme activity of purified variants p.Thr136Ile, p.Ala184Thr, and p.Asp260Gly was similar to that of wild-type CTRC, whereas variant p.Ser210Pro was inactive. The frame-shift variant p.Ser210Leufs∗? was not secreted but accumulated intracellularly, and induced endoplasmic reticulum stress, as judged by elevated mRNA levels of HSPA5 and DDIT3, and increased mRNA splicing of XBP1.

conclusionsCTRC variants p.Ser210Pro and p.Ser210Leufs∗? abolish CTRC function and should be classified as pathogenic. Mechanistically, variant p.Ser210Pro directly affects the amino acid at the bottom of the substrate-binding pocket while the frame-shift variant promotes misfolding and thereby blocks enzyme secretion. Importantly, 3 of the 5 novel CTRC variants proved to be benign, indicating that functional analysis is indispensable for reliable determination of pathogenicity and the correct interpretation of genetic test results.

Indexed as

ChymotrypsinEndoplasmic Reticulum Chaperone BiPGenetic TestingPancreatitis, ChronicAdolescentChildFemaleHEK293 CellsHumansMaleMutationTranscription Factor CHOPChymotrypsinchymotrypsin CDDIT3 protein, humanEndoplasmic Reticulum Chaperone BiPHSPA5 protein, humanTranscription Factor CHOPChronic pancreatitisChymotrypsinEndoplasmic reticulum stressVariant prediction

Identifiers

PMID38876922
PMCPMC11529566

What Socratic holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.