A laminopathic mutation disrupting lamin filament assembly causes disease-like phenotypes in Caenorhabditis elegans.
A laminopathic mutation disrupting lamin filament assembly causes disease-like phenotypes in Caenorhabditis elegans.
复制标题
DOI：
10.1091/mbc.e11-01-0064
复制
发表时间：
2011-08-01
影响因子：
3.3
通讯作者：
Gruenbaum Y
中科院分区：
文献类型：
--
作者：
Bank EM;Ben-Harush K;Wiesel-Motiuk N;Barkan R;Feinstein N;Lotan O;Medalia O;Gruenbaum Y
人LMNA突变导致Emery-Dreifuss肌营养不良;然而，突变对核纤层蛋白丝组装的影响与疾病表型之间的机制联系尚未建立。在这里，我们表明，核纤层蛋白丝结构的变化转化为秀丽隐杆线虫的疾病表型，通过改变核纤层的字符。人类LMNA基因突变是许多核纤层病疾病的基础，包括Emery-Dreifuss肌营养不良症（EDMD）;然而，突变对核纤层蛋白丝组装和疾病表型的影响之间的机制联系尚未建立。我们研究了秀丽隐杆线虫核纤层蛋白ΔK46突变体，其对应于人核纤层蛋白A和C中EDMD连锁的ΔK32。体外核纤层蛋白ΔK46细丝的冷冻电子断层扫描显示，二聚体头-尾聚合物的侧向组装发生了改变，这导致四聚体原丝的异常组织。绿色荧光蛋白（GFP）：在C. elegans与LEM-2沿着在胚后阶段的核聚集体中被发现。GFP：ΔK46还导致emerin远离核外围的错误定位，这与纯化的emerin在体外与核纤层蛋白ΔK46细丝缔合的能力降低一致。GFP：ΔK46动物存在运动缺陷和肌肉结构异常。这些结果表明，核纤层蛋白丝结构的变化可以通过改变核纤层蛋白的定位转化为疾病样表型，并提出了ΔK32核纤层蛋白突变如何导致人类EDMD的模型。
Mutations in human LMNA cause Emery-Dreifuss muscular dystrophy; however, a mechanistic link between the effect of mutations on lamin filament assembly and disease phenotype has not been established. Here we show that changes in lamin filament structure translate into disease phenotypes in Caenorhabditis elegans by altering the character of the nuclear lamina. Mutations in the human LMNA gene underlie many laminopathic diseases, including Emery-Dreifuss muscular dystrophy (EDMD); however, a mechanistic link between the effect of mutations on lamin filament assembly and disease phenotypes has not been established. We studied the ΔK46 Caenorhabditis elegans lamin mutant, corresponding to EDMD-linked ΔK32 in human lamins A and C. Cryo-electron tomography of lamin ΔK46 filaments in vitro revealed alterations in the lateral assembly of dimeric head-to-tail polymers, which causes abnormal organization of tetrameric protofilaments. Green fluorescent protein (GFP):ΔK46 lamin expressed in C. elegans was found in nuclear aggregates in postembryonic stages along with LEM-2. GFP:ΔK46 also caused mislocalization of emerin away from the nuclear periphery, consistent with a decreased ability of purified emerin to associate with lamin ΔK46 filaments in vitro. GFP:ΔK46 animals had motility defects and muscle structure abnormalities. These results show that changes in lamin filament structure can translate into disease-like phenotypes via altering the localization of nuclear lamina proteins, and suggest a model for how the ΔK32 lamin mutation may cause EDMD in humans.