C698R mutation in Lrsam1 gene impairs nerve regeneration in a CMT2P mouse model.
C698R mutation in Lrsam1 gene impairs nerve regeneration in a CMT2P mouse model.
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DOI：
10.1038/s41598-022-15902-3
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发表时间：
2022-07-16
影响因子：
4.6
通讯作者：
Hu, Bo
中科院分区：
文献类型：
--
作者：
Moiseev, Daniel;Wazir, Zafar;Liu, Donghao;Li, Jun;Hu, Bo
LRSAM1基因环结构域C694R错义突变导致显性遗传性多神经病变，Charcot-Marie-Tooth病2P （CMT2P）。我们通过CRISPR/Cas9技术建立并表征了Lrsam1C698R敲入小鼠模型。杂合子（Lrsam1+/C698R）和纯合子（Lrsam1C698/C698R）敲入小鼠在行为测试和神经传导研究中均表现出正常的运动功能。17月龄前的坐骨神经形态测量分析显示，突变体与野生型小鼠的轴突密度和髓鞘厚度无显著差异。与这些正常发现一致，突变体LRSAM1与rna结合蛋白（如FUS和G3BP1）之间的蛋白-蛋白相互作用在小鼠细胞中仍然存在，这与人类CMT2P细胞中这些蛋白之间的相互作用被破坏不同。然而，在挤压神经损伤后，Lrsam1+/C698R小鼠在恢复过程中复合神经动作电位和传导速度有轻微但有统计学意义的降低。因此，C698R突变导致小鼠神经再生轻度受损。我们推测，重复性神经损伤可能，至少部分地，导致CMT2P缓慢进行性轴突丧失。
Missense mutation C694R in the RING domain of the LRSAM1 gene results in a dominantly inherited polyneuropathy, Charcot-Marie-Tooth disease type 2P (CMT2P). We have generated and characterized a Lrsam1C698R knock-in mouse model produced through CRISPR/Cas9 technology. Both heterozygous (Lrsam1+/C698R) and homozygous (Lrsam1C698/C698R) knock-in mice exhibited normal motor functions on behavioral tests as well as normal on nerve conduction studies. Axonal density and myelin thickness were not significantly different between mutants and wild-type mice by sciatic nerve morphometric analysis up to 17 months of age. In line with these normal findings, protein–protein interactions between mutant LRSAM1 and RNA-binding proteins (such as FUS and G3BP1) were still present in mouse cells, which differs from the disrupted interactions between these proteins in human CMT2P cells. However, after crush nerve injury, Lrsam1+/C698R mice had a mild, but statistically significant, reduced compound nerve action potential and conduction velocity during recovery. Therefore, C698R mutation results in a mild impaired nerve regeneration in mice. We speculate that repetitive nerve injuries may, at least partially, contribute to the slowly progressive axonal loss in CMT2P.
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影响因子：
1.1
作者：
Menorca RM;Fussell TS;Elfar JC
通讯作者：
Elfar JC
影响因子：
4.5
作者：
Hu B;Arpag S;Zhang X;Möbius W;Werner H;Sosinsky G;Ellisman M;Zhang Y;Hamilton A;Chernoff J;Li J
通讯作者：
Li J
DOI：
10.1093/gerona/glu208
发表时间：
2015-11-01
影响因子：
5.1
作者：
Walsh, Michael E.;Sloane, Lauren B.;Van Remmen, Holly
通讯作者：
Van Remmen, Holly
DOI：
10.1007/s13311-021-01125-3
发表时间：
2021-10
期刊：
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
影响因子：
--
作者：
Arthur-Farraj P;Coleman MP
通讯作者：
Coleman MP
影响因子：
3.5
作者：
Weterman, Marian A. J.;Sorrentino, Vincenzo;Baas, Frank
通讯作者：
Baas, Frank