The common truncation variant in pancreatic lipase related protein 2 (PNLIPRP2) is expressed poorly and does not alter risk for chronic pancreatitis

Abstract

A nonsense variant (p.W358X) of human pancreatic lipase related protein 2 (PNLIPRP2) is present in different ethnic populations with a high allele frequency. In cell culture experiments, the truncated protein mainly accumulates inside the cells and causes endoplasmic reticulum stress. Here, we tested the hypothesis that variant p.W358X might increase risk for chronic pancreatitis through acinar cell stress. We sequenced exon 11 of PNLIPRP2 in a cohort of 256 subjects with chronic pancreatitis (152 alcoholic and 104 non-alcoholic) and 200 controls of Hungarian origin. We observed no significant difference in the distribution of the truncation variant between patients and controls. We analyzed mRNA expression in human pancreatic cDNA samples and found the variant allele markedly reduced. We conclude that the p.W358X truncation variant of PNLIPRP2 is expressed poorly and has no significant effect on the risk of chronic pancreatitis.

Fig 1. PNLIPRP2 variants in exon 11 and the flanking intronic regions identified in the present study.

The truncation variant is in bold type. The three haplotypes formed by the five commonly occurring variants are also shown.

Fig 2. Expression of the PNLIPRP2 p.W358X truncation variant.

A, Electropherogram of the genomic DNA sequence of a heterozygous carrier showing the double signal at the position of variants p.W358X and p.V362I. B, Electropherogram of the pancreatic cDNA sequence of the same heterozygous subject. Note the absence of the signal corresponding to the minor truncation allele at the position of the variants. C, Agarose gel electrophoresis of PCR amplicons from pancreatic cDNA samples of subjects with homozygous A (minor truncation allele) and G (full-length allele) genotypes. Control reaction was performed with no added template.

Fig 3. The effect of common PNLIPRP2 variants on mRNA expression in the pancreas.

Box plots were taken from the GTEx Portal (GTEx Analysis Release V7 - www.gtexportal.org). Note the diminished expression of the reference alleles (Ref), which correspond to the truncation haplotype in this database. See Table 1 for variant designation.