TY - JOUR
T1 - C698R mutation in Lrsam1 gene impairs nerve regeneration in a CMT2P mouse model
AU - Moiseev, Daniel
AU - Wazir, Zafar
AU - Liu, Donghao
AU - Li, Jun
AU - Hu, Bo
N1 - Funding Information:
The authors wish to thank Dr. Scott Millis for his assistance on statistics, Dr. Robert Burgess for his assistance in knock-in mouse production, and Perry Vera for his assistance in the Rotarod test. This research is supported by grants from the National Institute of Neurological Disorders and Stroke (R01NS115748) and the Department of Veterans Affairs (IBX003385A).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/7/16
Y1 - 2022/7/16
N2 - 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.
AB - 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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U2 - 10.1038/s41598-022-15902-3
DO - 10.1038/s41598-022-15902-3
M3 - Article
C2 - 35842440
AN - SCOPUS:85134402131
VL - 12
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 12160
ER -