| The identification of mutations underlying heritable peripheral neuropathies, diseases that affect the peripheral nervous system (PNS), has revealed that genes of diverse functions, and sometimes ubiquitous expression, are important to PNS development, maintenance, and pathology. This genetic heterogeneity makes predicting additional PNS disease genes difficult; therefore, forward genetics, which takes an unbiased, phenotype-driven approach to gene discovery, is a particularly suitable method for advancing understanding of the genetics of the PNS.;The mutant mouse strain 20884 arose on the C57B1/6J background during an ENU mutagenesis screen for recessive mutations. Mutant 20884 mice are characterized by hind limb dysfunction, which appears at 5 weeks as a floppy gait and progresses to paralysis by 6-7 weeks. Linkage mapping established the genetic basis of the phenotype as two linked mutations: a missense mutation in the phosphatidate phosphatase Lpin1 and a nonsense mutation in the neuronal cell adhesion molecule NrCAM. The Lpin120884 single mutant appears grossly wild type but is affected by a de/remyelinating neuropathy characterized by demyelination and redundant myelin visible in the sciatic nerve at 8 weeks and hind limb grip weakness at 10 weeks, but a significant improvement in both by 12 weeks. The NrCAM20884 mutant is characterized only by a mild reduction in conduction velocity. Sciatic nerve histology and morphometric analysis revealed that the Lpin1 20884 mutant and the double mutant are characterized by similar levels of demyelination and aberrant myelin structures. Nevertheless, the double mutant demonstrates a more dramatic onset of phenotype, as well as a lack of behavioral improvement at 12 weeks. It is proposed that the absence of NrCAM in a demyelinating environment either expedites the pathogenic mechanism, hinders the repair mechanism, or both, resulting in the development of an electrophysiological defect of a magnitude great enough to result in muscle atrophy and paralysis. Interestingly, despite the increased severity of its initial phenotype, the double mutant gradually recovers from paralysis after 16 weeks, showing gait improvement and an eventual return of the ability to grip in the hind paws. |
