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.

Identification of a Unique Transgenic Mouse Line That Develops Megabladder, Obstructive Uropathy, and Renal Dysfunction

“…A summation of the changes observed in BUN, creatinine, and bicarbonate provided the best prognostic marker of terminally ill mice. associated with a demyelinating peripheral neuropathy (30,31). Transgenic mice that overexpress human chorionic gonadotropin develop functional urethral obstruction that is associated with enlargement of prostates and seminal vesicles (32).…”

CD36: Implications in cardiovascular disease

“…CD36 is classified as a class B scavenger receptor (Platt, & Gordon, 1998,Krieger, 1997, and is part of a gene family that includes lysosomal integral membrane protein II (LIMP-II), which plays a role in nerve myelinization (Gamp, et al, 2003), CD36 and LIMP-II analogous-I protein (CLA-1) (known as scavenger receptor BI (SR-BI) in mice), which mediates the selective uptake of cholesterol esters from high density lipoprotein (HDL) (Acton, Rigotti, Landschulz, Xu, Hobbs, & Krieger, 1996), and Croquemorte, a drosophila protein, that phagocytoses apoptotic cells and senescent erythrocytes (Franc, Dimarcq, Lagueux, Hoffmann, & Ezekowitz, 1996,Franc, Heitzler, Ezekowitz, & White, 1999. Scavenger receptors are found in both primitive and immunologically advanced organisms and their continued evolutionary conservation suggest their important role at the forefront of the initial organism response to pathogens and in normal homeostasis (Krieger, 1997,Gordon, 2002.…”

Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophy

“…LIMP-2 contains two transmembrane domains, a cytoplasmic loop and two luminal glycosylated domains (23). It is known that lysosomal membrane proteins can shuttle between lysosomal and plasma membranes.…”