Discovery and functional annotation of PRSS1 promoter variants in chronic pancreatitis

Boulling, Arnaud, Abrantes, Amandine, Masson, Emmanuelle, Cooper, David Neil ORCID: https://orcid.org/0000-0002-8943-8484, Robaszkiewicz, Michel, Chen, Jian-Min and Férec, Claude 2016. Discovery and functional annotation of PRSS1 promoter variants in chronic pancreatitis. Human Mutation 37 (11) , pp. 1149-1152. 10.1002/humu.23053

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Abstract

Recently, our resequencing of the promoter region of PRSS1 in French Caucasian individuals led to the identification of a functional variant (c.-204C > A) that is in perfect linkage disequilibrium with the “chronic pancreatitis (CP)-protective” PRSS1 c.-408C > T variant. Here, we extended the resequencing to 626 French Caucasians (242 idiopathic CP patients and 384 controls). We discovered three additional variants (c.-184G > A, c.-173C > T, and c.-147C > T), each being found only once in either patients or controls. We analyzed these three variants, together with a known PRSS1 promoter variant (c.-30_-28delTCC) long considered to be causative for CP, by luciferase promoter reporter assay in AR42J cells treated with dexamethasone. This analysis revealed that c.-30_-28delTCC resulted in reduced rather than increased PRSS1 gene expression, suggesting that it is not a CP risk factor as originally claimed. We provide evidence that c.-147C > T probably confers protection against CP by reducing the affinity of an ATF4 transcription factor binding site.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	Q Science > QH Natural history > QH426 Genetics
Publisher:	Wiley-Blackwell
ISSN:	1059-7794
Date of First Compliant Deposit:	20 November 2017
Date of Acceptance:	14 July 2016
Last Modified:	18 Nov 2024 17:00
URI:	https://orca.cardiff.ac.uk/id/eprint/94705

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