Discovery and Functional Annotation of PRSS1 Promoter Variants in Chronic Pancreatitis

作者：Boulling Arnaud; Abrantes Amandine; Masson Emmanuelle; Cooper David N; Robaszkiewicz Michel; Chen Jian Min; Ferec Claude

来源：Human Mutation, 2016, 37(11): 1149-1152.

DOI：10.1002/humu.23053

• chronic pancreatitis
• electrophoretic mobility shift assay
• precision medicine
• promoter reporter gene assay
• supershift

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.

• 出版日期2016-11
• 单位河北医科大学