Chronic Pancreatitis: The True Pathogenic Culprit within the SPINK1 N34S-Containing Haplotype Is No Longer at Large.

Na Pu,Emmanuelle Génin,Claude Férec,David N Cooper,Jian-Min Chen,Emmanuelle Masson

doi:10.3390/genes12111683

Abstract

A diverse range of loss-of-function variants in the SPINK1 gene (encoding pancreatic secretory trypsin inhibitor) has been identified in patients with chronic pancreatitis (CP). The haplotype harboring the SPINK1 c.101A>G (p.Asn34Ser or N34S) variant (rs17107315:T>C) is one of the most important heritable risk factors for CP as a consequence of its relatively high prevalence worldwide (population allele frequency ≈ 1%) and its considerable effect size (odds ratio ≈ 11). The causal variant responsible for this haplotype has been intensively investigated over the past two decades. The different hypotheses tested addressed whether the N34S missense variant has a direct impact on enzyme structure and function, whether c.101A>G could affect pre-mRNA splicing or mRNA stability, and whether another variant in linkage disequilibrium with c.101A>G might be responsible for the observed association with CP. Having reviewed the currently available genetic and experimental data, we conclude that c.-4141G>T (rs142703147:C>A), which disrupts a PTF1L-binding site within an evolutionarily conserved HNF1A-PTF1L cis-regulatory module located ∼4 kb upstream of the SPINK1 promoter, can be designated as the causal variant beyond reasonable doubt. This case illustrates the difficulties inherent in determining the identity of the causal variant underlying an initially identified disease association.

Highlights

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The recognition of this pathway emerged from the identification and characterization of gain-of-function variants in PRSS1 and loss-of-function variants in SPINK1 and CTRC (encoding chymotrypsin C (MIM# 601405), which degrades all human trypsinogen/trypsin isoforms) in patients with the disease ([3,4,5] and references therein) (Figure 1)
A diverse range of variants in the SPINK1 gene has been reported in the literature [3,4]

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Chronic pancreatitis (CP) is a complex disease that can be caused by genetic and/or environmental factors ([1] and references therein). The recognition of this pathway emerged from the identification and characterization of gain-of-function variants in PRSS1 (encoding cationic trypsinogen; MIM# 276000) and loss-of-function variants in SPINK1 (encoding pancreatic secretory trypsin inhibitor; MIM# 167790) and CTRC (encoding chymotrypsin C (MIM# 601405), which degrades all human trypsinogen/trypsin isoforms) in patients with the disease ([3,4,5] and references therein) (Figure 1).

Results

Conclusion