Genetics of Proteasome Diseases

Aldrin V Gomes

doi:10.1155/2013/637629

Abstract

The proteasome is a large, multiple subunit complex that is capable of degrading most intracellular proteins. Polymorphisms in proteasome subunits are associated with cardiovascular diseases, diabetes, neurological diseases, and cancer. One polymorphism in the proteasome gene PSMA6 (−8C/G) is associated with three different diseases: type 2 diabetes, myocardial infarction, and coronary artery disease. One type of proteasome, the immunoproteasome, which contains inducible catalytic subunits, is adapted to generate peptides for antigen presentation. It has recently been shown that mutations and polymorphisms in the immunoproteasome catalytic subunit PSMB8 are associated with several inflammatory and autoinflammatory diseases including Nakajo-Nishimura syndrome, CANDLE syndrome, and intestinal M. tuberculosis infection. This comprehensive review describes the disease-related polymorphisms in proteasome genes associated with human diseases and the physiological modulation of proteasome function by these polymorphisms. Given the large number of subunits and the central importance of the proteasome in human physiology as well as the fast pace of detection of proteasome polymorphisms associated with human diseases, it is likely that other polymorphisms in proteasome genes associated with diseases will be detected in the near future. While disease-associated polymorphisms are now readily discovered, the challenge will be to use this genetic information for clinical benefit.

Highlights

Over the last decade, significant improvements have been made in genotyping efficiency, sequencing technology, and statistical methodology, providing researchers with better opportunities to define the role of sequence variation in the development of human diseases [1,2,3]
Several disease-associated and promising diseaserelated candidate genes have been determined for diseases ranging from cardiovascular diseases to immune diseases
The known number of polymorphisms associated with disease and the number of diseases associated with polymorphisms are both likely to rise significantly over the decade

Summary

Introduction

Significant improvements have been made in genotyping efficiency, sequencing technology, and statistical methodology, providing researchers with better opportunities to define the role of sequence variation in the development of human diseases [1,2,3]. Two other 20S proteasome genes, PSMA8 and PSMB11 (codes for β5t), which occur in specific tissues, were recently reported but are not currently known to be associated with any diseases [33, 34]. Two haplotypes in the chromosomal region (five SNPs in a 100 kb region of chromosome 14) encompassing KIAA0391 and PSMA6 genes, 1A-2G-3C-4A-5A and 1A-2G3G-4A-5A, show increased risk of both CAD and myocardial infarction (MI), while another haplotype, 1T-2G-3C-4G-5A, showed decreased risk of CAD and MI [85] These latter results suggest that disease risk factor determination may be improved by investigating haplotypes instead of SNPs. Other recent experimental data suggest that haplotypes are more predictive than individual SNPs at determining risk factors for complex diseases [90]. Table shows only disease-associated polymorphisms for which the SNP or amino acid change is known

Immunoproteasome Mutations and Polymorphisms

Polymorphism Associated with Reduced Risk of Disease

Gene-Environment Interactions

Findings

Conclusions