LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice.
In previous overexpression studies we revealed a role for the lysosomal membrane protein LIMP-2/LGP85 in lysosomal biogenesis. LIMP-2-deficient mice show an increased postnatal mortality which is associated with a development of a uni- or bilateral hydronephrosis caused by an obstruction of the ureteropelvic junction. An accumulation of lysosomes in epithelial cells of the ureter adjacent to the ureteral lumen and a disturbed apical expression of uroplakin was observed, suggesting an impairment of membrane transport processes. Serious hearing impairment in LIMP-2-deficient animals was indicated by deficits in acoustic startle responses, in brainstem evoked auditory potentials and a reduced endochondral potential. LIMP-2-deficient mice suffer from a massive decline of spiral ganglia in the cochlea concomitant with that of the inner and outer hair cells. These pathological changes begin at the age of 3 months and are probably secondary to a degeneration of the stria vascularis. LIMP-2-deficient mice are also characterized by a peripheral demyelinating neuropathy. Demyelinization was found to be associated with a massive loss of peripheral myelin proteins and an increased activity and expression of lysosomal proteins highlighting a hitherto unknown role of the lysosomal compartment in the development of this myelination disorder. The phenotype of LIMP-2-deficient mice stimulates the search for mutations in human disorders associated with degeneration of the stria vascularis and/or demyelinization of peripheral nerves.
Pubmed ID: 12620969 RIS Download
Animals | Animals, Newborn | Antigens, CD36 | Biological Transport | Blotting, Southern | Blotting, Western | Cathepsin D | Cell Membrane | Cochlea | Deafness | Demyelinating Diseases | Epithelial Cells | Evoked Potentials, Auditory | Exons | Fibroblasts | Genotype | Hypertrophy | Kidney | Lysosome-Associated Membrane Glycoproteins | Lysosomes | Membrane Glycoproteins | Membrane Proteins | Mice | Mice, Inbred C57BL | Mice, Knockout | Mice, Mutant Strains | Mice, Transgenic | Microscopy, Electron | Microscopy, Fluorescence | Models, Genetic | Mutation | Peripheral Nervous System Diseases | Phenotype | Receptors, Scavenger | Recombination, Genetic | Reverse Transcriptase Polymerase Chain Reaction | Sialoglycoproteins | Subcellular Fractions | Time Factors | Tissue Distribution | Transgenes | Ureter | Urinary Bladder | Urothelium