DelK32-lamin A/C has abnormal location and induces incomplete tissue maturation and severe metabolic defects leading to premature death
DelK32-lamin A/C has abnormal location and induces incomplete tissue maturation and severe metabolic defects leading to premature death
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DOI：
10.1093/hmg/ddr534
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发表时间：
2012-03-01
影响因子：
3.5
通讯作者：
Bonne, Gisele
中科院分区：
文献类型：
--
作者：
Bertrand, Anne T.;Renou, Laure;Bonne, Gisele
LMNA基因编码层蛋白A/C中间丝，这些中间丝在核膜下聚合，也存在于核质中，以一种未知的组装状态存在。它们被认为通过与转录因子的相互作用在信号通路中具有结构功能和调节作用。LMNA突变与许多遗传性人类疾病有关，包括严重先天性肌营养不良症(L-先天性肌营养不良症)。我们创造了含有L-CMD突变的LmNA(K32)敲入小鼠。LMNA(K32/K32)小鼠表现出横纹肌成熟延迟和代谢缺陷，包括脂肪组织减少和低血糖导致过早死亡。突变蛋白在Lmna(K32/K32)中的水平明显较低，在胚胎发育过程中，野生型层粘连蛋白A/C蛋白逐渐从核质灶向核缘转移，突变蛋白保持在核质灶中。在肝脏和脂肪细胞分化过程中，K32-lamin A/C的表达改变了固醇调节元件结合蛋白1(SREBP-1)的转录活性。综上所述，我们的结果表明，核层层蛋白A/C的重新定位可能通过释放其对转录因子(包括但不限于SREBP-1)的抑制功能，对组织成熟具有重要意义。重要的是，L-CMD患者应该接受推定的代谢紊乱调查。
The LMNA gene encodes lamin A/C intermediate filaments that polymerize beneath the nuclear membrane, and are also found in the nucleoplasm in an uncharacterized assembly state. They are thought to have structural functions and regulatory roles in signaling pathways via interaction with transcription factors. Mutations in LMNA have been involved in numerous inherited human diseases, including severe congenital muscular dystrophy (L-CMD). We created the Lmna(K32) knock-in mouse harboring a L-CMD mutation. Lmna(K32/K32) mice exhibited striated muscle maturation delay and metabolic defects, including reduced adipose tissue and hypoglycemia leading to premature death. The level of mutant proteins was markedly lower in Lmna(K32/K32), and while wild-type lamin A/C proteins were progressively relocated from nucleoplasmic foci to the nuclear rim during embryonic development, mutant proteins were maintained in nucleoplasmic foci. In the liver and during adipocyte differentiation, expression of K32-lamin A/C altered sterol regulatory element binding protein 1 (SREBP-1) transcriptional activities. Taken together, our results suggest that lamin A/C relocation at the nuclear lamina seems important for tissue maturation potentially by releasing its inhibitory function on transcriptional factors, including but not restricted to SREBP-1. And importantly, L-CMD patients should be investigated for putative metabolic disorders.