Leukoencephalopathy and early death associated with an Ashkenazi-Jewish founder mutation in the Hikeshi gene
Leukoencephalopathy and early death associated with an Ashkenazi-Jewish founder mutation in the Hikeshi gene
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DOI：
10.1136/jmedgenet-2015-103232
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发表时间：
2016-02-01
影响因子：
4
通讯作者：
Elpeleg, Orly
中科院分区：
文献类型：
--
作者：
Edvardson, Simon;Kose, Shingo;Elpeleg, Orly
背景脑白质营养不良是影响髓鞘形成或维持的遗传性白色物质疾病。在最近发现的遗传缺陷与脑白质营养不良，几个基因会聚在一个共同的机制，涉及蛋白质转录/翻译和ER stress response.Methods的遗传基础上的一种新的先天性脑白质营养不良，与早发性痉挛性下肢轻瘫，获得性小头畸形和视神经萎缩进行了研究，在6例患者从三个无关的德系犹太人家庭。为此，我们使用了纯合性作图，外显子组分析，蛋白质印迹，（Hikeshi，HSF 1-pS326和b-肌动蛋白），间接免疫荧光（HSP 70和HSF 1），将表达Hikeshi或EGFP的质粒核注射到患者成纤维细胞中，结果所有患者均为错义突变p.Val54Leu纯合子，在C11 ORF 73编码HSP 70核转运蛋白，Hikeshi。这种突变与家族中的疾病分离，由1：200的德系犹太人携带。该突变与患者成纤维细胞中检测不到的Hikeshi水平以及热休克应激期间核HSP 70的缺乏相关，这是一种在将正常人Hikeshi引入患者细胞后逆转的现象。Hikeshi在小鼠脑中央白色物质中表达。结论Hikeshi在HSP 70向核内迁移中起重要作用。很可能在没有Hikeshi的情况下，HSP 70不能减弱多重热休克诱导的核表型，使细胞在热休克应激期间不受保护。我们推测，三个突然死亡的六名患者后，短期发热性疾病和危及生命的心肌心包炎的第四个是由于过量的核外HSP 70水平，启动细胞因子释放或提供目标的自然杀伤细胞。另外，核HSP 70可能在应激细胞保护中发挥积极作用。
Background Leukodystrophies are genetic white matter disorders affecting the formation or maintenance of myelin. Among the recently discovered genetic defects associated with leukodystrophies, several genes converge on a common mechanism involving protein transcription/translation and ER stress response.Methods The genetic basis of a novel congenital leukodystrophy, associated with early onset spastic paraparesis, acquired microcephaly and optic atrophy was studied in six patients from three unrelated Ashkenazi-Jewish families. To this end we used homozygosity mapping, exome analysis, western blot (Hikeshi, HSF1-pS326 and b-actin) in patient fibroblasts, indirect immunofluorescence (HSP70 and HSF1) in patient fibroblasts undergoing heat shock stress, nuclear injection of plasmids expressing Hikeshi or EGFP in patient fibroblasts, in situ hybridization and Immunoblot analysis of Hikeshi in newborn and adult mouse brain.Results All the patients were homozygous for a missense mutation, p. Val54Leu, in C11ORF73 encoding HSP70 nuclear transporter protein, Hikeshi. The mutation segregated with the disease in the families and was carried by 1: 200 Ashkenazi-Jewish individuals. The mutation was associated with undetectable level of Hikeshi in the patients' fibroblasts and with lack of nuclear HSP70 during heat shock stress, a phenomenon which was reversed upon the introduction of normal human Hikeshi to the patients cells. Hikeshi was found to be expressed in central white matter of mouse brain.Conclusions These data underscore the importance of Hikeshi for HSP70 relocation into the nucleus. It is likely that in the absence of Hikeshi, HSP70 cannot attenuate the multiple heat shock induced nuclear phenotypes, leaving the cells unprotected during heat shock stress. We speculate that the sudden death of three of the six patients following a short febrile illness and the life-threatening myo-pericarditis in the fourth are the result of excess extra-nuclear HSP70 level which initiates cytokine release or provide target for natural killer cells. Alternatively, nuclear HSP70 might play an active role in stressed cells protection.