C698R mutation in Lrsam1 gene impairs nerve regeneration in a CMT2P mouse model

July 16, 2022

Daniel Moiseev (1), Zafar Wazir (1), Donghao Liu (1), Jun Li (1) (2) (3) (4), Bo Hu (1) (4)
Science Reports. (16 July 2022). DOI: https://doi.org/10.1038/s41598-022-15902-3


Genetics of the nervous system, neuroscience, peripheral nervous system, regeneration and repair in the nervous system


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.

How Our Software Was Used

Bright field images were automatically segmented with a deep model trained in Dragonfly. Dragonfly’s Region of Interest analysis tool was then used to measure each fiber’s inner and outer areas from the segmented myelin and inner axonal areas.

Author Affiliation

(1) Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USA
(2) Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
(3) John D. Dingell VA Medical Center, Detroit, MI, USA
(4) Department of Neurology, Houston Methodist Research Institute, Houston, TX, USA