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.
Gamp
Alexander-Christian
AC
Zentrum Biochemie und Molekulare Zellbiologie, Abt. Biochemie II, Universität Göttingen, 37073 Göttingen, Germany.
Tanaka
Yoshitaka
Y
Lüllmann-Rauch
Renate
R
Wittke
Dorothee
D
D'Hooge
Rudi
R
De Deyn
Peter P
PP
Moser
Tobias
T
Maier
Hannes
H
Hartmann
Dieter
D
Reiss
Karina
K
Illert
Anna-Lena
AL
von Figura
Kurt
K
Saftig
Paul
P
D000818:Animals; D000831:Animals, Newborn; D001692:Biological Transport; D015139:Blotting, Southern; D015153:Blotting, Western; D018955:CD36 Antigens / Q000235:genetics* / Q000502:physiology; D002402:Cathepsin D / Q000096:biosynthesis; D002462:Cell Membrane; D003051:Cochlea / Q000378:metabolism / Q000473:pathology; D003638:Deafness / Q000235:genetics*; D003711:Demyelinating Diseases / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D005072:Evoked Potentials, Auditory; D005091:Exons; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D006984:Hypertrophy; D007668:Kidney / Q000378:metabolism; D051907:Lysosomal Membrane Proteins; D008247:Lysosomes / Q000378:metabolism; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009154:Mutation; D010523:Peripheral Nervous System Diseases / Q000235:genetics*; D010641:Phenotype; D051116:Receptors, Scavenger; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D019076:Transgenes; D014513:Ureter / Q000378:metabolism; D001743:Urinary Bladder / Q000378:metabolism; D019459:Urothelium / Q000473:pathology
D018955:CD36 Antigens; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D051116:Receptors, Scavenger; C074299:SCARB2 protein, human; C489452:Scarb2 protein, mouse; D012795:Sialoglycoproteins; D002402:Cathepsin D