PSMB8 Encoding the β5i Proteasome Subunit Is Mutated in Joint Contractures, Muscle Atrophy, Microcytic Anemia, and Panniculitis-Induced Lipodystrophy Syndrome

Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, 75390, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 12/2010; 87(6):866-72. DOI: 10.1016/j.ajhg.2010.10.031
Source: PubMed

ABSTRACT We performed homozygosity mapping in two recently reported pedigrees from Portugal and Mexico with an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP). This revealed only one homozygous region spanning 2.4 Mb (5818 SNPs) on chromosome 6p21 shared by all three affected individuals from both families. We directly sequenced genes involved in immune response located in this critical region, excluding the HLA complex genes. We found a homozygous missense mutation c.224C>T (p.Thr75Met) in the proteasome subunit, beta-type, 8 (PSMB8) gene in affected patients from both pedigrees. The mutation segregated in an autosomal-recessive fashion and was not detected in 275 unrelated ethnically matched healthy subjects. PSMB8 encodes a catalytic subunit of the 20S immunoproteasomes called β5i. Immunoproteasome-mediated proteolysis generates immunogenic epitopes presented by major histocompatibility complex (MHC) class I molecules. Threonine at position 75 is highly conserved and its substitution with methionine disrupts the tertiary structure of PSMB8. As compared to normal lymphoblasts, those from an affected patient showed significantly reduced chymotrypsin-like proteolytic activity mediated by immunoproteasomes. We conclude that mutations in PSMB8 cause JMP syndrome, most probably by affecting MHC class I antigen processing.

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Available from: Heloisa G Santos, Dec 17, 2013
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    • "JMP syndrome (autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy) patients show hepatosplenomegaly and hypergammaglobulinemia as well as lipodystrophy of the arms, face, and thorax. Using genome-wide homozygosity mapping, a homozygous missense mutation (c.224C > T, Thr75Met) in the proteasome gene PSMB8 that encodes the β5i (LMP7) subunit was detected in two pedigrees from Portugal and Mexico with JMP syndrome [54]. Segregation of this mutation in other members of the pedigrees occurred in an autosomal-recessive fashion. "
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    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.
    12/2013; 2013(1):637629. DOI:10.1155/2013/637629
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    • "Most (N = 28) of the reported patients carried homozygous mutations in the Proteasome Subunit, Beta-Type, 8 (PSMB8) gene [53,54,56,57]. This gene encodes β5i, a catalytic subunit of the immunoproteasome, an intracellular protease complex specialized for degradation of polyubiquitinated proteins. "
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    ABSTRACT: Monogenic autoinflammatory diseases are a group of hereditary disorders characterized by a clinical and biological inflammatory syndrome in which there is little or no evidence of autoimmunity. The discovery of the first causative gene in 1997 was rapidly followed by the identification of many others from the same group. The mutated proteins can be directly or indirectly involved in the regulation of inflammation. The available literature includes numerous reviews, which address the principle diseases, but we wanted to focus on the most recent rare syndromes. A comprehensive review is thus provided, including taxonomic, genetic, and epidemiological data, along with characteristics defining positive and differential diagnoses and treatment. We believe that this update will assist physicians in correctly naming their patient's illness. This is an essential step for the effective and targeted management of an orphan disease.
    Orphanet Journal of Rare Diseases 10/2013; 8(1):162. DOI:10.1186/1750-1172-8-162 · 3.36 Impact Factor
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    • "PSMB8 has been identified by three different groups looking at patients who were classified as having three differently named diseases. Agarwal et al studied patients with joint contractures, muscle atrophy, microcytic anaemia, and panniculitis-induced lipodystrophy syndrome (JMP) using homozygosity mapping and parametric multipoint linkage based on SNP genotypes from the Illumina HumanOmni1-Quad Beadchip [29]. Arima et al performed homozygosity mapping in five unrelated patients and three unaffected siblings of one of the patients with Nakajo-Nishimura Syndrome (NNS) using Affymetrix GeneChip Human Mapping 500K array set [30]; whilst Kitamura et al used homozygosity mapping and multipoint linkage to study Japanese autoinflammatory syndrome with lipodystrophy (JASL) patients and unaffected siblings from 2 consanguineous families genotyped on the Illumina Human 610 Quad combined with exome sequencing [31]. "
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    ABSTRACT: Steady progress in our understanding of the genetic basis of autoinflammatory diseases has been made over the past 16 years. Since the discovery of the familial Mediterranean fever gene MEFV (also known as marenostrin) in 1997, 18 other genes responsible for monogenic autoinflammatory diseases have been identified to date. The discovery of these genes was made through the utilisation of many genetic mapping techniques, including next generation sequencing platforms. This review article clearly describes the gene hunting approaches, methods of data analysis and the technological platforms used, which has relevance to all those working within the field of gene discovery for Mendelian disorders.
    09/2013; 3(1):32. DOI:10.1186/2045-7022-3-32
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