LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice

Abstract

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.

Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease

“…Cells were transiently transfected using TurboFect™ following the manufacturer's instructions. LIMP-2 mice were previously described in Gamp et al [21].…”

Expression of the Transmembrane Lysosomal Protein SCARB2/Limp-2 in Renin Secretory Granules Controls Renin Release

“…The generation of Limp-2 -/- mice has been described previously [12], and all animals used were on a mixed 129Sv/Bl6 background of the same generation. Both sexes were used in almost identical numbers in each comparable group.…”

Current perspectives on congenital obstructive nephropathy

“…Congenital progressive hydronephrosis and a hereditary condition in male C57BL/ KsJ mice have been shown to produce ureteral obstruction following birth [81,82]. Mice with the targeted deletion of a disintegrin and metalloproteinase with thrombospondin motifs, lysosomal membrane protein LIMP-2/LGP85, and calcineurin also develop urinary tract obstruction in the postnatal period [83][84][85]. Transgenic mice overexpressing human chorionic gonadotropin develop functional urethral obstruction that is not apparent until adulthood [86].…”