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


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
    • "For example, mutations in AGPAT2, BSCL2, CAV1, and PTRF are associated with congenital generalized lipodystrophies; mutations in LMNA, PPARG, AKT2, PLIN1, and CIDEC with familial partial lipodystrophies and mutations in LMNA and ZMPSTE24 are reported in patients with Hutchinson–Gilford progeria and mandibuloacral dysplasia associated lipodystrophies [Garg, 2013]. Recently, mutations in PSMB8, PCYT1A, PIK3R1, FOS, and POLD1 have been reported in patients with extremely rare subtypes of lipodystrophies [Agarwal et al., 2010; Dyment et al., 2013; Knebel et al., 2013; Thauvin-Robinet et al., 2013; Weedon et al., 2013; Payne et al., 2014]. Despite this progress, molecular basis of many extremely rare lipodystrophy patients with distinctive phenotypes remains unclear. "
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    ABSTRACT: Despite remarkable progress in identifying causal genes for many types of genetic lipodystrophies in the last decade, the molecular basis of many extremely rare lipodystrophy patients with distinctive phenotypes remains unclear. We conducted whole exome sequencing of the parents and probands from six pedigrees with neonatal onset of generalized loss of subcutaneous fat with additional distinctive phenotypic features and report de novo heterozygous null mutations, c.424C>T (p.Q142*) and c.479_480delTT (p.F160*), in CAV1 in a 7-year-old male and a 3-year-old female of European origin, respectively. Both the patients had generalized fat loss, thin mottled skin and progeroid features at birth. The male patient had cataracts requiring extraction at age 30 months and the female patient had pulmonary arterial hypertension. Dermal fibroblasts of the female patient revealed negligible CAV1 immunofluorescence staining compared to control but there were no differences in the number and morphology of caveolae upon electron microscopy examination. Based upon the similarities in the clinical features of these two patients, previous reports of CAV1 mutations in patients with lipodystrophies and pulmonary hypertension, and similar features seen in CAV1 null mice, we conclude that these variants are the most likely cause of one subtype of neonatal onset generalized lipodystrophy syndrome. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Apr 2015 · American Journal of Medical Genetics Part A
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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.
    Full-text · Article · Dec 2013
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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.
    Full-text · Article · Oct 2013 · Orphanet Journal of Rare Diseases
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