Functional predictors of pathogenicity of missense <i>CPA1</i> variants in chronic pancreatitis

Abstract

We read with great interest the recent article by Zhu et al. [1], demonstrating that misfolding of pancreatic lipase due to an inborn mutation causes chronic pancreatitis (CP).Variants in the CPA1 gene, encoding procarboxypeptidase A1, can elicit CP by the same mechanism, however, not all variants are alike, and correct prediction of benign versus pathogenic behavior has been challenging.In 2013, rare heterozygous variants in CPA1 were identified in multiple cohorts of CP cases [2].Functional analysis indicated that patients preferentially carried loss-offunction CPA1 variants, most of which were poorly secreted or not secreted at all from transfected cells.When examined in aggregate, loss-of-function CPA1 variants were significantly overrepresented in cases versus controls, with higher prevalence in early-onset disease.Individually, however, only three loss-of-function missense variants (p.N256K, p.Y308H, p.R382W) showed significant enrichment in CP.Disease-association could not be ascertained for the majority of variants due to their ultra-low frequency.Variant p.N256K was characterized functionally in detail using HEK 293T cells, AR42J cells, and a knock-in mouse model [2][3][4].The experiments revealed that p.N256K triggered CP in mice and caused loss of proenzyme secretion, intracellular retention, and increased endoplasmic reticulum (ER) stress in cellular models and mice.The findings suggested that CP develops in carriers of p.N256K due to mutation-induced proenzyme misfolding and consequent ER stress.Subsequent reports described rare CPA1 variants p.V251M, p.S282P, and p.K374E in hereditary CP, confirming their pathogenic nature and high penetrance

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