Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases.
Drosophila Models Reveal Properties of Mutant Lamins That Give Rise to Distinct Diseases.
复制标题
果蝇模型揭示了引起不同疾病的突变核纤层蛋白的特性。
作者：
LMNA基因的突变导致一系列被称为核纤层蛋白病的疾病，包括肌营养不良、脂肪营养不良和早发性衰老综合征。LMNA基因编码A型核纤层蛋白，核纤层蛋白A/C，形成内核膜下的网状结构的中间丝。核纤层蛋白具有保守的结构域结构，其由头部、卷曲螺旋杆和具有Ig样折叠的C-末端尾部结构域组成。这项研究确定了两种突变核纤层蛋白之间的差异，导致不同的临床疾病。其中一个LMNA突变编码核纤层蛋白A/C p.R527P，另一个编码核纤层蛋白A/C p.R482W，它们通常分别与肌营养不良和脂肪营养不良相关。为了确定这些突变如何不同地影响肌肉，我们在果蝇核纤层蛋白C（LamC）基因（人类LMNA的直系同源物）中产生了等同的突变。肌肉特异性表达的R527 P等价物显示胞质聚集的LamC，减少幼虫肌肉大小，减少幼虫的运动性，和心脏缺陷，导致减少成年人的寿命。相比之下，肌肉特异性表达的R482 W等同物导致异常的核形状，而幼虫肌肉大小，幼虫运动性和成年寿命的变化相比，控制。总的来说，这些研究确定了导致临床上不同表型的突变核纤层蛋白性质的根本差异，为疾病机制提供了见解。
Mutations in the LMNA gene cause a collection of diseases known as laminopathies, including muscular dystrophies, lipodystrophies, and early-onset aging syndromes. The LMNA gene encodes A-type lamins, lamins A/C, intermediate filaments that form a meshwork underlying the inner nuclear membrane. Lamins have a conserved domain structure consisting of a head, coiled-coil rod, and C-terminal tail domain possessing an Ig-like fold. This study identified differences between two mutant lamins that cause distinct clinical diseases. One of the LMNA mutations encodes lamin A/C p.R527P and the other codes lamin A/C p.R482W, which are typically associated with muscular dystrophy and lipodystrophy, respectively. To determine how these mutations differentially affect muscle, we generated the equivalent mutations in the Drosophila Lamin C (LamC) gene, an orthologue of human LMNA. The muscle-specific expression of the R527P equivalent showed cytoplasmic aggregation of LamC, a reduced larval muscle size, decreased larval motility, and cardiac defects resulting in a reduced adult lifespan. By contrast, the muscle-specific expression of the R482W equivalent caused an abnormal nuclear shape without a change in larval muscle size, larval motility, and adult lifespan compared to controls. Collectively, these studies identified fundamental differences in the properties of mutant lamins that cause clinically distinct phenotypes, providing insights into disease mechanisms.
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影响因子：
3.3
作者：
Bawa S;Gameros S;Baumann K;Brooks DS;Kollhoff JA;Zolkiewski M;Re Cecconi AD;Panini N;Russo M;Piccirillo R;Johnson DK;Kashipathy MM;Battaile KP;Lovell S;Bouyain SEA;Kawakami J;Geisbrecht ER
通讯作者：
Geisbrecht ER
DOI：
10.1016/j.bbrc.2021.02.102
发表时间：
2021-03-09
影响因子：
3.1
作者：
Ahn, Jinsook;Lee, Jinwook;Ha, Nam-Chul
通讯作者：
Ha, Nam-Chul
DOI：
10.1007/978-1-4939-6371-3_2
发表时间：
2016-01-01
期刊：
DROSOPHILA: METHODS AND PROTOCOLS, 2ND EDITION
影响因子：
--
作者：
Caygill, Elizabeth E.;Brand, Andrea H.
通讯作者：
Brand, Andrea H.
DOI：
10.1016/j.bbadis.2018.11.010
发表时间：
2019-07-01
影响因子：
6.2
作者：
Blice-Baum，Anna C.;Guida，Maria Clara;Cammarato，Anthony
通讯作者：
Cammarato，Anthony
影响因子：
3.7
作者：
Al-Haboubi, Teiba;Shumaker, Dale K.;Fahrenkrog, Birthe
通讯作者：
Fahrenkrog, Birthe