Human Molecular Genetics, 2003, Vol. 12, No. 6 631-646
© 2003 Oxford University Press
LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice
1Zentrum Biochemie und Molekulare Zellbiologie, Abt. Biochemie II, Universität Göttingen, 37073 Göttingen, Germany, 2Kyushu University, Graduate School of Pharmaceutical Sciences, Pharmaceutical Cell Biology, Fukuoka, Japan, 3Anatomisches Institut, Universität Kiel, Kiel, Germany, 4Laboratory of Neurochemistry and Behaviour, Born-Bunge Foundation, University of Antwerp, Belgium, 5Department of Otolaryngology, University of Göttingen, D-37075 Göttingen, Germany, 6Department of Otolaryngology, University of Hamburg, D-20246 Hamburg, Germany, 7Center for Human Genetics, K.U. Leuven and Flanders Interuniversity Institute for Biotechnology VIB 4, Herestraat 49, 3000 Leuven, Belgium and 8Department of Biochemistry, University Kiel, D-24098 Kiel, Germany
Received November 4, 2002; Accepted January 10, 2003
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.
* To whom correspondence should be addressed. Tel: +49 431 8802216; Fax: +49 431 8802238; Email: psaftig{at}biochem.uni-kiel.de
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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