Pathogenic Mutations Cause Rapid Degradation of Lysosomal Storage Disease-related Membrane Protein CLN6
Pathogenic Mutations Cause Rapid Degradation of Lysosomal Storage Disease-related Membrane Protein CLN6
复制标题
DOI：
10.1002/humu.21184
复制
发表时间：
2010-02-01
期刊：
影响因子：
3.9
通讯作者：
Braulke, Thomas
中科院分区：
文献类型：
--
作者：
Kurze, Anna-Katherina;Galliciotti, Giovanna;Braulke, Thomas
晚期婴儿神经元蜡样质脂褐质沉积症的一种变体形式是由CLN 6基因突变引起的常染色体隐性遗传神经变性溶酶体贮积症。定位于内质网的多位CLN 6膜蛋白的功能是未知的。在这里，我们报告了三个突变（c.368G>A，c. 460- 462 delATC，c.316insC）分别影响跨膜结构域3（p.Gly123Asp）、胞质环2（p.Ile154del）或导致截短的膜蛋白（p.Arg106ProfsX26）。突变CLN 6蛋白的合成速率和稳定性以突变依赖性方式降低。没有突变阻止CLN 6多肽的二聚化。p.Arg106ProfsX26突变体的特别快速的降解与该疾病的nclf小鼠模型中的鼠直系同源物Cln 6基因中的突变相同，可以被蛋白酶体和部分地被溶酶体蛋白酶抑制剂强烈抑制。两种降解途径似乎都足以防止突变型CLN 6多肽在内质网中的积累/聚集。(C)2009威利-利斯公司
One variant form of late infantile neuronal ceroid lipofuscinosis is an autosomal recessive inherited neurodegenerative lysosomal storage disorder caused by mutations in the CLN6 gene. The function of the polytopic CLN6 membrane protein localized in the endoplasmic reticulum is unknown. Here we report on expression studies of three mutations (c.368G>A, c. 460-462delATC, c.316insC) found in CLN6 patients predicted to affect transmembrane domain 3 (p.Gly123Asp), cytoplasmic loop 2 (p.Ile154del) or result in a truncated membrane protein (p.Arg106ProfsX26), respectively. The rate of synthesis and the stability of the mutant CLN6 proteins are reduced in a mutation-dependent manner. None of the mutations prevented the dimerization of the CLN6 polypeptides. The particularly rapid degradation of the p.Arg106ProfsX26 mutant which is identical with the mutation in the murine orthologue Cln6 gene in the nclf mouse model of the disease, can be strongly inhibited by proteasomal and partially by lysosomal protease inhibitors. Both degradative pathways seem to be sufficient to prevent the accumulation/aggregation of the mutant CLN6 polypeptides in the endoplasmic reticulum. (C) 2009 Wiley-Liss, Inc.