Concurrent Lpin1 and Nrcam mouse mutations result in severe peripheral neuropathy with transitory hindlimb paralysis.
Peripheral neuropathy is a broad category of disorders with a diverse etiology, grouped together by their common pathogenic effect on the peripheral nervous system (PNS). Because of the heterogeneity observed to be responsible for these disorders, a forward genetics method of gene discovery was used to identify additional affected pathways. In this report, we describe the mutant mouse line 20884, generated by N-ethyl-N-nitrosourea mutagenesis, which is characterized by adult-onset transitory hindlimb paralysis. Linkage mapping revealed that two point mutations are responsible for the phenotype: a partial loss-of-function mutation in the gene for phosphatidate phosphatase Lpin1 and a truncation mutation in the gene that encodes the neuronal cell adhesion molecule NrCAM. To investigate how the 20884 Lpin1 and Nrcam mutations interact to produce the paralysis phenotype, the double mutant and both single mutants were analyzed by quantitative behavioral, histological, and electrophysiological means. The Lpin1(20884) mutant and the double mutant are characterized by similar levels of demyelination and aberrant myelin structures. Nevertheless, the double mutant exhibits more severe electrophysiological abnormalities than the Lpin1(20884) mutant. The Nrcam(20884) mutant is characterized by normal sciatic nerve morphology and a mild electrophysiological defect. Comparison of the double mutant phenotype with the two single mutants does not point to an additive relationship between the two defects; rather, the Lpin1(20884) and Nrcam(20884) defects appear to act synergistically to produce the 20884 phenotype. It is proposed that the absence of NrCAM in a demyelinating environment has a deleterious effect, possibly by impairing the process of remyelination.
Douglas
Darlene S
DS
Department of Neurology, Jack Miller Center for Peripheral Neuropathy, The University of Chicago, Chicago, Illinois 60637, USA.
Moran
Jennifer L
JL
Bermingham
John R
JR
Chen
Xiang-Jun
XJ
Brindley
David N
DN
Soliven
Betty
B
Beier
David R
DR
Popko
Brian
B
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics*; D006614:Hindlimb; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010264:Paraplegia / Q000235:genetics* / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000503:physiopathology; D010711:Phosphatidate Phosphatase
D015815:Cell Adhesion Molecules; C491151:Nrcam protein, mouse; D009687:Nuclear Proteins; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase