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

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

Dynamics of multiple sexual signals in relation to climatic conditions

Question: Can trait-specific phenotypic plasticity in response to annual environmental variation lead to changes in the strength of sexual selection through the relative expression of sexual ornaments at the population level? Data description: We recorded breeding dates and the sizes of white forehead and wing patches of male collared flycatchers (Ficedula albicollis) from 1998 to 2005 in a nestboxbreeding population in the Pilis Mountains, Hungary. As environmental predictors, we used the North Atlantic Oscillation (NAO) index and local weather data, classified as direct or indirect effects relative to the moult of the given ornament. Search method: First, we used general linear mixed models to assess environmental effects on the within-individual changes and absolute yearly sizes of forehead and wing patches. We then used similar models to determine whether the relative sizes of the two plumage traits at the population level varied among years. Finally, we used multiple regressions to establish if the relative yearly expression of an ornament affected standardized sexual selection gradients on this ornament in the given year. Conclusions: Within-individual changes in forehead and wing patch size were predicted by the climate of their moulting season (winter and summer, respectively). There was also an indirect effect of previous winter climate on changes in wing patch size. Environmental effects on the absolute expression of ornaments at the population level followed the within-individual patterns. The relative population-level expression of forehead and wing patches fluctuated significantly among years. Sexual selection on a given ornament increased with its relative expression in that year

Yolk androstenedione, but not testosterone, predicts offspring fate and reflects parental quality

Yolk androgen deposition is a widely investigated maternal effect in birds, but its adaptive value is at present unclear. The offspring fitness correlates of natural yolk androgen levels are virtually unknown, whereas manipulations largely focused on testosterone and neglected other androgens. We determined yolk concentrations of the 2 dominant androgens, androstenedione and testosterone, from all eggs in collared flycatcher clutches and followed the fate of individual offspring from these eggs in a crossfostering experiment. Yolk concentration of androstenedione was much higher than that of testosterone. Offspring from eggs with relatively higher androstenedione concentrations within a clutch were relatively large after hatching, grew slower thereafter, and had a higher recruitment rate in subsequent years. The increase of androstenedione with laying order and its within-clutch variance were negatively correlated with a condition-dependent female ornament, perhaps indicating compensatory hormone deposition into later hatching eggs by females in low condition. Yolk testosterone variation within or among clutches was not related to any measured aspect of offspring or parental quality. Our results suggest that in some species, especially those with much more androstenedione than testosterone in the yolk, androstenedione and not testosterone may be the yolk androgen with a long-term function and adaptive deposition pattern.</p

Mesotrypsin Signature Mutation in a Chymotrypsin C (CTRC) Variant Associated with Chronic Pancreatitis

Human chymotrypsin C (CTRC) protects against pancreatitis by degrading trypsinogen and thereby curtailing harmful intra-pancreatic trypsinogen activation. Loss-of-function mutations in CTRC increase the risk for chronic pancreatitis. Here we describe functional analysis of eight previously uncharacterized natural CTRC variants tested for potential defects in secretion, proteolytic stability, and catalytic activity. We found that all variants were secreted from transfected cells normally, and none suffered proteolytic degradation by trypsin. Five variants had normal enzymatic activity, whereas variant p.R29Q was catalytically inactive due to loss of activation by trypsin and variant p.S239C exhibited impaired activity possibly caused by disulfide mispairing. Surprisingly, variant p.G214R had increased activity on a small chromogenic peptide substrate but was markedly defective in cleaving bovine β-casein or the natural CTRC substrates human cationic trypsinogen and procarboxypeptidase A1. Mutation p.G214R is analogous to the evolutionary mutation in human mesotrypsin, which rendered this trypsin isoform resistant to proteinaceous inhibitors and conferred its ability to cleave these inhibitors. Similarly to the mesotrypsin phenotype, CTRC variant p.G214R was inhibited poorly by eglin C, ecotin, or a CTRC-specific variant of SGPI-2, and it readily cleaved the reactive-site peptide bonds in eglin C and ecotin. We conclude that CTRC variants p.R29Q, p.G214R, and p.S239C are risk factors for chronic pancreatitis. Furthermore, the mesotrypsin-like CTRC variant highlights how the same natural mutation in homologous pancreatic serine proteases can evolve a new physiological role or lead to pathology, determined by the biological context of protease function

Risk of chronic pancreatitis in carriers of loss-of-function CTRC variants: A meta-analysis

The digestive protease chymotrypsin C (CTRC) protects the pancreas against pancreatitis by degrading potentially harmful trypsinogen. Loss-of-function genetic variants in CTRC increase risk for chronic pancreatitis (CP) with variable effect size, as judged by the reported odds ratio (OR) values. Here, we performed a meta-analysis of published studies on four variants that alter the CTRC amino-acid sequence, are clinically relatively common (global carrier frequency in CP >1%), reproducibly showed association with CP and their loss of function phenotype was verified experimentally. We found strong enrichment of CTRC variants p.A73T, p.V235I, p.K247_R254del, and p.R245W in CP cases versus controls, yielding OR values of 6.5 (95% confidence interval (CI) 2.4-17.8), 4.5 (CI 2.2-9.1), 5.4 (CI 2.6-11.0), and 2.6 (CI 1.6-4.2), respectively. Subgroup analysis demonstrated disease association of variants p.K247_R254del and p.R245W in alcoholic CP with similar effect sizes as seen in the overall CP group. Homozygosity or compound heterozygosity were rare and seemed to be associated with higher risk. We also identified a so far unreported linkage disequilibrium between variant p.K247_R254del and the common c.180C>T (p.G60 =) haplotype. Taken together, the results indicate that heterozygous loss-of-function CTRC variants increase the risk for CP approximately 3-7-fold. This meta-analysis confirms the clinical significance of CTRC variants and provides further justification for the genetic screening of CP patients