Disease relevance of Mpv17

• Adult mice homozygous for the Mpv17 integration developed nephrotic syndrome and chronic renal failure [1].
• Glomerular overproduction of oxygen radicals in Mpv17 gene-inactivated mice causes podocyte foot process flattening and proteinuria: A model of steroid-resistant nephrosis sensitive to radical scavenger therapy [2].
• It also provides evidence for the functional conservation of the Mpv17 gene in mammals and points to a potential role of this gene in human kidney disease [3].
• The germ line insertion of a defective retrovirus into the Mpv17 gene of mice is associated with a recessive phenotype [3].
• Indeed, our study revealed that Mpv17-/- mice developed significant systemic hypertension and tachycardia between 4 weeks and 5 months of age, accompanied by polyuria and elevated natriuresis [4].

High impact information on Mpv17

• Loss of the Mpv17 protein does not impair peroxisome biogenesis but instead leads to a reduced ability to produce reactive oxygen species (ROS) [5].
• The mutant mouse strain Mpv17 carries a retroviral insert in its genome which inactivates the Mpv17 gene [5].
• Here evidence is provided that glomerular damage in this murine model is due to overproduction of oxygen radicals and accumulation of lipid peroxidation adducts that were found in isolated glomeruli of Mpv17-/- mice [2].
• The development of glomerular disease in Mpv17-/- mice was inhibited by scavengers of oxygen radicals (dithiomethylurea) and lipid peroxidation (probucol), but not by steroid treatment [2].
• Expression of the recessive glomerulosclerosis gene Mpv17 regulates MMP-2 expression in fibroblasts, the kidney, and the inner ear of mice [6].

Chemical compound and disease context of Mpv17

• SYM1 is the stress-induced Saccharomyces cerevisiae ortholog of the mammalian kidney disease gene Mpv17 and is required for ethanol metabolism and tolerance during heat shock [7].

Biological context of Mpv17

• In our search of a common mediator exerting effects on several aspects of the phenotype, we discovered that the absence of the Mpv17 gene product causes a strong increase in matrix metalloproteinase 2 (MMP-2) expression [6].
• Mpv17-like protein (M-LP) has been identified as a new protein that shows high sequence homology with Mpv17 protein, a peroxisomal membrane protein involved in the development of early onset glomerulosclerosis [8].
• Since Mpv17 protein contributes to ROS homeostasis, further studies are necessary to elucidate downstream signaling molecules activated by ROS [9].
• Search of the protein domain family database (ProDom) revealed that M-LP is a new member of the Mpv17 domain family (PD008400) [10].
• These studies explain the cellular responses to missing Mpv17-protein, such as accumulation of the extracellular matrix, degeneration, and apoptosis in the inner ear [9].

Anatomical context of Mpv17

• The recessive mouse mutant Mpv17 is characterized by the development of early-onset glomerulosclerosis, concomitant hypertension, and structural alterations of the inner ear [6].
• This was seen in the kidney and cochlea of Mpv17-negative mice as well as in tissue culture cells derived from these animals [6].
• A novel alternative spliced Mpv17-like protein isoform localizes in cytosol and is expressed in a kidney- and adult-specific manner [8].
• The severe sensorineural hearing loss and degenerative changes of the cochlear structures indicate that cochlear structures, especially the outer hair cells and the intermediate cells of the stria vascularis, are vulnerable to the missing Mpv17 gene product [11].
• In contrast to the peroxisomal localization of Mpv17, we find that Sym1 is an integral membrane protein of the inner mitochondrial membrane [7].

Associations of Mpv17 with chemical compounds

• These results indicate that the glomerular disease in Mpv17-/- mice qualifies as a model of steroid-resistant focal segmental glomerulosclerosis and that experimental therapies with scavengers of oxygen radicals and lipid peroxidation efficiently ameliorate glomerular damage [2].
• Expression of Mpv17 in ylr251wdelta cells complements the 37 degrees C ethanol growth defect, suggesting that these proteins are functional orthologs [7].

Other interactions of Mpv17

• In Mpv17-/- cells, enzyme activity and mRNA expression (examined by quantitative RT-PCR) of membrane-bound gamma-glutamyl transpeptidase were increased, while plasma glutathione peroxidase and superoxide dismutase levels were lowered [12].

Analytical, diagnostic and therapeutic context of Mpv17

• Sequence analyses of the mouse and human genes also revealed the presence of a previously identified gene, Mpv17, in the 5' region upstream of the urocortin gene [13].
• Thus, the Mpv17 gene is a recessive disease gene in mice and this mouse strain is a potential animal model for glomerular diseases in man [14].
• We here show that this gene, which has a role in the production of reactive oxygen species, can rescue the phenotype of Mpv17 deficient mice when introduced by transgenesis [3].

References