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The Journal of Neuroscience, September 30, 2009, 29(39):12089-12100; doi:10.1523/JNEUROSCI.2029-09.2009

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Neurobiology of Disease
Concurrent Lpin1 and Nrcam Mouse Mutations Result in Severe Peripheral Neuropathy with Transitory Hindlimb Paralysis

Darlene S. Douglas,^1,2 Jennifer L. Moran,³ John R. Bermingham Jr,⁴ Xiang-Jun Chen,¹ David N. Brindley,⁵ Betty Soliven,¹ David R. Beier,³ and Brian Popko^1,2

¹Jack Miller Center for Peripheral Neuropathy, Department of Neurology, and ²Committee on Genetics, Genomics, & Systems Biology, The University of Chicago, Chicago, Illinois 60637, ³Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, ⁴McLaughlin Research Institute, Great Falls, Montana 59405, and ⁵Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

Correspondence should be addressed to Brian Popko, Jack Miller Center for Peripheral Neuropathy, Department of Neurology, The University of Chicago, 5841 South Maryland Avenue, MC2030, Chicago, IL 60637. Email: bpopko{at}uchicago.edu

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 Lpin1²⁰⁸⁸⁴ 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 Lpin1²⁰⁸⁸⁴ mutant. The Nrcam²⁰⁸⁸⁴ 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 Lpin1²⁰⁸⁸⁴ and Nrcam²⁰⁸⁸⁴ 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.

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Received April 29, 2009; revised July 1, 2009; accepted Aug. 3, 2009.

Correspondence should be addressed to Brian Popko, Jack Miller Center for Peripheral Neuropathy, Department of Neurology, The University of Chicago, 5841 South Maryland Avenue, MC2030, Chicago, IL 60637. Email: bpopko{at}uchicago.edu

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