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Discovery and functional annotation of PRSS1 promoter variants in chronic pancreatitis

Boulling, Arnaud, Abrantes, Amandine, Masson, Emmanuelle, Cooper, David Neil, 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: 08 Dec 2017 09:17
URI: http://orca.cf.ac.uk/id/eprint/94705

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