Nijmegen breakage syndrome: the clearance pathway for mutant nibrin protein is allele specific.
Nijmegen breakage syndrome: the clearance pathway for mutant nibrin protein is allele specific.
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奈梅亨断裂综合征：突变尼布蛋白的清除途径是等位基因特异性的
DOI：
10.1016/j.gene.2013.02.033
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发表时间：
2013
期刊：
影响因子：
3.5
通讯作者：
Digweed M
中科院分区：
文献类型：
--
作者：
Salewsky B;Wessendorf P;Hirsch D;Krenzlin H;Digweed M
常染色体隐性遗传病Nijmegen breaking syndrome （NBS）是由编码nibrin蛋白的NBN基因突变引起的（NBS1; p95）。在大多数情况下，一个5bp的缺失，一个奠基者突变，在翻译的替代起始后导致一个低形态的70kD蛋白p70-nibrin。蛋白质水平与疾病的临床病程有关，特别是与恶性肿瘤有关。在这里，研究了突变蛋白清除的机制和效率，以确定这些是否对nibrin丰度有影响。用蛋白酶体和溶酶体抑制剂处理NBS患者细胞系和逆转录病毒转导剂，并用半定量免疫印迹法检测p70-nibrin和p95-nibrin水平。结果表明，p70-nibrin在来自不同NBS患者的细胞系中被蛋白酶体以不同的效率降解，导致该部分活性蛋白片段的稳态水平或低或高。相比之下，先前描述的NBN错义突变，由于色氨酸取代关键精氨酸而扰乱蛋白质折叠，被发现被溶酶体微自噬清除，也导致细胞水平降低。数据显示，截断的尼布林和错误折叠的尼布林具有不同的清除途径。
The autosomal recessive disorder Nijmegen breakage syndrome (NBS) is caused by mutations in the NBN gene which codes for the protein nibrin (NBS1; p95). In the majority of cases, a 5bp deletion, a founder mutation, leads to a hypomorphic 70kD protein, p70-nibrin, after alternative initiation of translation. Protein levels are of relevance for the clinical course of the disease, particularly with regard to malignancy. Here, mechanisms and efficiency of mutant protein clearance were examined in order to establish whether these have an impact on nibrin abundance. Cell lines from NBS patients and retroviral transductants were treated with proteasome and lysosome inhibitors and examined by semi-quantitative immunoblotting for p70-nibrin and p95-nibrin levels. The results show that p70-nibrin is degraded by the proteasome with varying efficiency in cell lines from different NBS patients leading to lower or higher steady state levels of this partially active protein fragment. In contrast, a previously described NBN missense mutation, which disturbs protein folding due to the substitution of a critical arginine by tryptophan, was found to be cleared by lysosomal microautophagy leading also to lower cellular levels. The data show that truncated nibrin and misfolded nibrin have different clearance pathways.
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奈梅亨断裂综合征 (V2) 的基因并不位于 11 号染色体上。
影响因子：
9.8
作者：
K. Komatsu;S. Matsuura;H. Tauchi;S. Endo;S. Kodama;D. Smeets;C. Weemaes;M. Oshimura
通讯作者：
M. Oshimura
影响因子：
5.3
作者：
Crosslin DR;McDavid A;Weston N;Nelson SC;Zheng X;Hart E;de Andrade M;Kullo IJ;McCarty CA;Doheny KF;Pugh E;Kho A;Hayes MG;Pretel S;Saip A;Ritchie MD;Crawford DC;Crane PK;Newton K;Li R;Mirel DB;Crenshaw A;Larson EB;Carlson CS;Jarvik GP;Electronic Medical Records and Genomics (eMERGE) Network
通讯作者：
Electronic Medical Records and Genomics (eMERGE) Network
影响因子：
56.9
作者：
Matsuoka, Shuhei;Ballif, Bryan A.;Elledge, Stephen J.
通讯作者：
Elledge, Stephen J.
影响因子：
4.7
作者：
Krueger, Lars;Demuth, Ilja;Digweed, Martin
通讯作者：
Digweed, Martin
影响因子：
4.3
作者：
Kanu, Nnennaya;Behrens, Axel
通讯作者：
Behrens, Axel