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Int. J. Mol. Sci. 2016, 17(12), 2148; doi:10.3390/ijms17122148

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

1
Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118, USA
2
First Department of Surgery, Semmelweis University, 1082 Budapest, Hungary
3
Institute for Translational Medicine, University of Pécs, 7624 Pécs, Hungary
4
First Department of Medicine, University of Szeged, 6720 Szeged, Hungary
5
First Department of Medicine, University of Pécs, 7624 Pécs, Hungary
6
Department of Gastroenterology, St. George Teaching Hospital of County Fejér, 8000 Székesfehérvár, Hungary
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editors: Srikumar Chellappan and Jaya Padmanabhan
Received: 7 November 2016 / Revised: 14 December 2016 / Accepted: 14 December 2016 / Published: 20 December 2016
(This article belongs to the Special Issue Pancreatic Disorders)
View Full-Text   |   Download PDF [1057 KB, uploaded 21 December 2016]   |  

Abstract

Human chymotrypsin-like elastases 3A and 3B (CELA3A and CELA3B) are the products of gene duplication and share 92% identity in their primary structure. CELA3B forms stable complexes with procarboxypeptidases A1 and A2 whereas CELA3A binds poorly due to the evolutionary substitution of Ala241 with Gly in exon 7. Since position 241 is polymorphic both in CELA3A (p.G241A) and CELA3B (p.A241G), genetic analysis can directly assess whether individual variability in complex formation might alter risk for chronic pancreatitis. Here we sequenced exon 7 of CELA3A and CELA3B in a cohort of 225 subjects with chronic pancreatitis (120 alcoholic and 105 non-alcoholic) and 300 controls of Hungarian origin. Allele frequencies were 2.5% for CELA3A p.G241A and 1.5% for CELA3B p.A241G in controls, and no significant difference was observed in patients. Additionally, we identified six synonymous variants, two missense variants, a gene conversion event and ten variants in the flanking intronic regions. Variant c.643-7G>T in CELA3B showed an association with alcoholic chronic pancreatitis with a small protective effect (OR = 0.59, 95% CI = 0.39–0.89, p = 0.01). Functional analysis of missense variants revealed no major defects in secretion or activity. We conclude that variants affecting amino-acid position 241 in CELA3A and CELA3B are not associated with chronic pancreatitis, indicating that changes in complex formation between proelastases and procarboxypeptidases do not alter pancreatitis risk. View Full-Text
Keywords: pancreas; chronic pancreatitis; digestive protease; zymogen complexes; elastase pancreas; chronic pancreatitis; digestive protease; zymogen complexes; elastase
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Párniczky, A.; Hegyi, E.; Tóth, A.Z.; Szücs, Á.; Szentesi, A.; Vincze, Á.; Izbéki, F.; Németh, B.C.; Hegyi, P.; Sahin-Tóth, M. Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis. Int. J. Mol. Sci. 2016, 17, 2148.

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