LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice
LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice
复制标题
DOI：
10.1093/hmg/ddg062
复制
发表时间：
2003-03-15
影响因子：
3.5
通讯作者：
Saftig, P
中科院分区：
文献类型：
--
作者：
Gamp, AC;Tanaka, Y;Saftig, P
在之前的过表达研究中，我们揭示了溶酶体膜蛋白 LIMP-2/LGP85 在溶酶体生物发生中的作用。 LIMP-2缺陷小鼠表现出出生后死亡率增加，这与肾盂输尿管连接部阻塞引起的单侧或双侧肾积水的发生有关。观察到输尿管管腔附近的输尿管上皮细胞中溶酶体的积累以及尿斑蛋白顶端表达的紊乱，表明膜运输过程受损。 LIMP-2缺陷动物的严重听力损伤表现为声惊吓反应、脑干诱发听觉电位和软骨内电位降低的缺陷。 LIMP-2 缺陷小鼠的耳蜗螺旋神经节以及内毛细胞和外毛细胞均大幅衰退。这些病理变化在 3 个月大时开始，可能继发于血管纹退化。 LIMP-2缺陷型小鼠的特征还在于周围脱髓鞘神经病。脱髓鞘被发现与周围髓鞘蛋白的大量损失以及溶酶体蛋白的活性和表达增加有关，这凸显了溶酶体区室在这种髓鞘形成疾病的发展中迄今为止未知的作用。LIMP-2缺陷小鼠的表型刺激了对与血管纹变性和/或周围神经脱髓鞘相关的人类疾病中的突变的研究。
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 vascularls. 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.