LMNA variants cause cytoplasmic distribution of nuclear pore proteins in Drosophila and human muscle.
LMNA variants cause cytoplasmic distribution of nuclear pore proteins in Drosophila and human muscle.
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LMNA 变异导致果蝇和人类肌肉中核孔蛋白的细胞质分布。
DOI：
10.1093/hmg/ddr592
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发表时间：
2012-04-01
影响因子：
3.5
通讯作者：
Wallrath LL
中科院分区：
文献类型：
--
作者：
Dialynas G;Flannery KM;Zirbel LN;Nagy PL;Mathews KD;Moore SA;Wallrath LL
编码A型核纤层蛋白的人LMNA基因的突变引起核纤层蛋白病，其包括几种类型的肌营养不良。在这里，LMNA中的杂合序列变体，导致单个氨基酸取代，在表现出肌无力的患者中被鉴定。为了评估替换是否改变核纤层蛋白功能，我们使用果蝇模型进行了体内分析。产生表达果蝇A型核纤层蛋白的突变体形式的原种，所述突变体形式在每个变体之后建模。幼虫用于运动性测定和体壁肌肉的组织化学染色。同时，对患者的人肌肉活检样本进行免疫组织化学分析。在对照果蝇中，肌肉特异性表达的野生型A型核纤层蛋白没有明显的影响。与此相反，突变体A型核纤层蛋白的表达导致显性幼虫肌肉缺陷和半致死蛹阶段。组织化学染色结果显示，突变体A型核纤层蛋白、B型核纤层蛋白、Sad1p蛋白、Klaroid蛋白和核孔复合体蛋白均定位于胞质。此外，细胞质肌动蛋白丝紊乱，表明核纤层和细胞骨架之间的联系被破坏。患者的肌肉活检显示与果蝇幼虫相似的营养不良性组织病理学和结构异常，包括核膜蛋白的细胞质分布。这些数据提供的证据表明，果蝇模型可用于评估新的LMNA突变的功能，并支持核蛋白的细胞区室化的损失有助于肌肉疾病的发病机制的想法。
Mutations in the human LMNA gene, encoding A-type lamins, give rise to laminopathies, which include several types of muscular dystrophy. Here, heterozygous sequence variants in LMNA, which result in single amino-acid substitutions, were identified in patients exhibiting muscle weakness. To assess whether the substitutions altered lamin function, we performed in vivo analyses using a Drosophila model. Stocks were generated that expressed mutant forms of the Drosophila A-type lamin modeled after each variant. Larvae were used for motility assays and histochemical staining of the body-wall muscle. In parallel, immunohistochemical analyses were performed on human muscle biopsy samples from the patients. In control flies, muscle-specific expression of the wild-type A-type lamin had no apparent affect. In contrast, expression of the mutant A-type lamins caused dominant larval muscle defects and semi-lethality at the pupal stage. Histochemical staining of larval body wall muscle revealed that the mutant A-type lamin, B-type lamins, the Sad1p, UNC-84 domain protein Klaroid and nuclear pore complex proteins were mislocalized to the cytoplasm. In addition, cytoplasmic actin filaments were disorganized, suggesting links between the nuclear lamina and the cytoskeleton were disrupted. Muscle biopsies from the patients showed dystrophic histopathology and architectural abnormalities similar to the Drosophila larvae, including cytoplasmic distribution of nuclear envelope proteins. These data provide evidence that the Drosophila model can be used to assess the function of novel LMNA mutations and support the idea that loss of cellular compartmentalization of nuclear proteins contributes to muscle disease pathogenesis.
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影响因子：
4.4
作者：
Fidzianska, A;Hausmanowa-Petrusewicz, I
通讯作者：
Hausmanowa-Petrusewicz, I
DOI：
10.1073/pnas.83.17.6450
发表时间：
1986-09-01
影响因子：
11.1
作者：
FISHER, DZ;CHAUDHARY, N;BLOBEL, G
通讯作者：
BLOBEL, G
影响因子：
2.7
作者：
Ainsley, Joshua A.;Kim, Myung Jun;Johnson, Wayne A.
通讯作者：
Johnson, Wayne A.
影响因子：
3.5
作者：
De Vos, Winnok H.;Houben, Frederik;Broers, Jos L. V.
通讯作者：
Broers, Jos L. V.
影响因子：
4.6
作者：
Dialynas, George;Speese, Sean;Wallrath, Lori L.
通讯作者：
Wallrath, Lori L.