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Recently, we reported the identification of a functional PRSS1 promoter variant in perfect linkage disequilibrium (LD) with the chronic pancreatitis (CP)-‘protective’ rs10273639.1 This, together with several other recent papers published in Gut,2–4 underscored the importance of functional analysis for improving our understanding of the underlying pathophysiological mechanisms and also more fundamentally for establishing the clinical relevance or otherwise of CP-associated variants from the outset. In many diseases, in vitro functional analysis often represents the only practical means to determine the pathogenicity of patient-derived sequence variants, particularly when they are rare. Herein, we present a new and successful example in the context of CP.
SPINK1 is one of the most extensively studied CP genes, with >100 variants being reported to date.5 Of 19 known intronic variants, the four in LD with the p.Asn34Ser variant have been functionally analysed in the context of both minigene6 and full-length genomic sequence7; none had any detectable effect on pre-mRNA splicing. In addition, the functional consequences of the c.194+2T>C splice donor site variant …
WBZ and AB contributed equally.
Contributors ZL, Z-SL, CF and J-MC designed and directed the study. W-BZ and AB performed functional analysis. All authors interpreted the data, revised the manuscript and approved the final manuscript. J-MC wrote the manuscript with contributions from W-BZ and AB.
Funding W-BZ is a joint PhD student between Changhai Hospital and INSERM U1078 and received a 1-year scholarship from the China Scholarship Council (No. 201403170271). Support for this study came from the National Natural Science Foundation of China (Grant Nos 81470884, 81422010[ZL]), the Shanghai Rising-Star Program (Grant No. 13QA1404600[ZL]), the Conseil Régional de Bretagne, the Association des Pancréatites Chroniques Héréditaires, the Association de Transfusion Sanguine et de Biogénétique Gaetan Saleun and the Institut National de la Santé et de la Recherche Médicale (INSERM).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ethical Committee of the University of Brest.
Provenance and peer review Not commissioned; internally peer reviewed.
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