Anders Molven and colleagues show that a recombined allele of the lipase gene CEL and its pseudogene CELP confers susceptibility to chronic pancreatitis. The hybrid allele is associated with approximately fivefold-higher risk of disease, and it encodes a protein with reduced lipolytic activity and prominent intracellular accumulation. Carboxyl ester lipase is a digestive pancreatic enzyme encoded by the CEL gene1. Mutations in CEL cause maturity-onset diabetes of the young as well as pancreatic exocrine dysfunction2. Here we describe a hybrid allele (CEL-HYB) originating from a crossover between CEL and its neighboring pseudogene, CELP. In a discovery series of familial chronic pancreatitis cases, we observed CEL-HYB in 14.1% (10/71) of cases compared to 1.0% (5/478) of controls (odds ratio (OR) = 15.5; 95% confidence interval (CI) = 5.1–46.9; P = 1.3 × 10−6 by two-tailed Fisher's exact test). In three replication studies of nonalcoholic chronic pancreatitis, we identified CEL-HYB in a total of 3.7% (42/1,122) cases and 0.7% (30/4,152) controls (OR = 5.2; 95% CI = 3.2–8.5; P = 1.2 × 10−11; formal meta-analysis). The allele was also enriched in alcoholic chronic pancreatitis. Expression of CEL-HYB in cellular models showed reduced lipolytic activity, impaired secretion, prominent intracellular accumulation and induced autophagy. These findings implicate a new pathway distinct from the protease-antiprotease system of pancreatic acinar cells in chronic pancreatitis.

Mitochondrial dysfunction and altered proteostasis are central features of neurodegenerative diseases. The pitrilysin metallopeptidase 1 (PITRM1) is a mitochondrial matrix enzyme, which digests oligopeptides, including the mitochondrial targeting sequences that are cleaved from proteins imported across the inner mitochondrial membrane and the mitochondrial fraction of amyloid beta (Aβ). We identified two siblings carrying a homozygous PITRM1 missense mutation (c.548G>A, p.Arg183Gln) associated with an autosomal recessive, slowly progressive syndrome characterised by mental retardation, spinocerebellar ataxia, cognitive decline and psychosis. The pathogenicity of the mutation was tested in vitro, in mutant fibroblasts and skeletal muscle, and in a yeast model. A Pitrm1^+/− heterozygous mouse showed progressive ataxia associated with brain degenerative lesions, including accumulation of Aβ‐positive amyloid deposits. Our results show that PITRM1 is responsible for significant Aβ degradation and that impairment of its activity results in Aβ accumulation, thus providing a mechanistic demonstration of the mitochondrial involvement in amyloidotic neurodegeneration. Synopsis A clinically peculiar neurodegenerative disorder in humans was indentified and shown to be caused by a pathogenic homozygous mutation in PITRM1, encoding an oligopeptidase of the mitochondrial inner compartment. The neuropathology of a PITRM1^−/+ mouse provides genetic evidence that Aβ is present within mitochondria, and demonstrates a link between impaired PITRM1 activity and Aβ amyloidotic neurodegeneration in mammals. A homozygous disease segregating missense mutation was found in the PITRM1 gene in two siblings of a consanguineous family. The pathogenic role of the mutation, causing PITRM1 instability, was validated by in vitro assay, characterization of mutant fibroblasts from patients and in PITRM1 knocked‐down human fibroblasts, and in a mutant yeast model. A hemizygous PITRM1 knockout mouse displayed reduced amount of PITRM1, associated with slowly progressive neurodegeneration, hallmarked by accumulation of Aβ amyloid in the brain.

Background: Mitochondrial dysfunction plays a key role in PD, but the underlying molecular mechanisms remain unresolved. We hypothesized that the disruption of mitochondrial function in PD is primed by rare, protein‐altering variation in nuclear genes controlling mitochondrial structure and function.Objective: The objective of this study was to assess whether genetic variation in genes associated with mitochondrial function influences the risk of idiopathic PD.Methods: We employed whole‐exome sequencing data from 2 independent cohorts of clinically validated idiopathic PD and controls, the Norwegian ParkWest cohort (n = 411) and the North American Parkinson's Progression Markers Initiative (n = 640). We applied burden‐based and variance‐based collapsing methods to assess the enrichment of rare, nonsynonymous, and damaging genetic variants on genes, exome‐wide, and on a comprehensive set of mitochondrial pathways, defined as groups of genes controlling specific mitochondrial functions.Results: Using the sequence kernel association test, we detected a significant polygenic enrichment of rare, nonsynonymous variants in the gene‐set encoding the pathway of mitochondrial DNA maintenance. Notably, this was the strongest association in both cohorts and survived multiple testing correction (ParkWest P = 6.3 × 10⁻³, Parkinson's Progression Markers Initiative P = 6.9 × 10⁻⁵, metaanalysis P = 3.2 × 10⁻⁶).Conclusions: Our results show that the enrichment of rare inherited variation in the pathway controlling mitochondrial DNA replication and repair influences the risk of PD. We propose that this polygenic enrichment contributes to the impairment of mitochondrial DNA homeostasis, thought to be a key mechanism in the pathogenesis of PD, and explains part of the disorder's “missing heritability.” © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Pasteurization of donated human milk preserves it for storage and makes it safe for feeding, but at the expense of its composition, nutritional values and functions. Here, we aimed to investigate the impact of Holder Pasteurization (HoP) and High Pressure Processing (HPP) methods on miRNA in human milk and to evaluate impact of these changes on miRNA functions. Milk samples obtained from women in 50^th day of lactation (n = 3) were subjected either to HoP, HPP or remained unpasteurized as a control. Subsequently, miRNA was isolated from whole material and exosomal fraction and sequenced with Illumina NextSeq 500. Sequencing data were processed, read counts were mapped to miRNA and analyzed both quantitatively with DESeq2 and functionally with DIANA mirPath v.3. While HPP caused statistically insignificant decrease in number of miRNA reads compared to unprocessed material, HoP led to 82-fold decrease in whole material (p = 0.0288) and 302-fold decrease in exosomes (p = 0.0021) not leaving enough reads for further analysis. Changes in composition of miRNA fraction before and after HPP indicated uneven stability of individual miRNAs under high pressure conditions, with miR-30d-5p identified as relatively stable and miR-29 family as sensitive to HPP. Interestingly, about 2/3 of unprocessed milk miRNA content consists of only 10 distinct miRNAs with miR-148a-3p at the top. Functional analysis of most abundant human milk miRNAs showed their involvement in signaling pathways, cell communication, proliferation and metabolism that are obviously important in rapidly growing infants. Functions of miRNAs which suffered the greatest depletion during HPP were similar to roles of the majority of unprocessed human milk’s miRNA, which indicates that those functions may be weakened although not completely lost. Our findings indicate that HPP is less detrimental to human milk miRNAs than HoP and should be considered in further research on recommended processing procedures for human milk banks.