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

Alexander Christian Gamp, Yoshitaka Tanaka, Renate Lüllmann-Rauch, Dorothee Wittke, Rudi D'Hooge, Peter P. De Deyn, Tobias Moser, Hannes Maier, Dieter Hartmann, Karina Reiss, Anna Lena Illert, Kurt von Figura, Paul Saftig

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Abstract

In previous overexpession 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.

Original languageEnglish
Pages (from-to)631-646
Number of pages16
JournalHuman Molecular Genetics
Volume12
Issue number6
DOIs
Publication statusPublished - Mar 15 2003

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Gamp, A. C., Tanaka, Y., Lüllmann-Rauch, R., Wittke, D., D'Hooge, R., De Deyn, P. P., Moser, T., Maier, H., Hartmann, D., Reiss, K., Illert, A. L., von Figura, K., & Saftig, P. (2003). LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice. Human Molecular Genetics, 12(6), 631-646. https://doi.org/10.1093/hmg/ddg062