Peripheral neuropathies are an important health problem for the American population. While peripheral neuropathies are commonly caused by diabetes and chemotherapy agents, a genetic-neuropathy, Charcot- Marie-Tooth disease (CMT), is the most common inherited neurologic disorder in people. CMT disease affects about 1 in 2,500 people in the USA. Symptoms of CMT are variable, but generally include chronic muscle weakness, foot deformities and limb muscle atrophy. Currently, there is no disease-modifying treatment for any CMT subtype. CMT is associated with mutations in genes that encode proteins involved in a variety of functions linked with myelination and axonal physiology. These mutations ultimately lead to impaired motor and sensory nerve function. Over 50 genes have been associated with CMT, although 4 genes (PMP22, MPZ, GJB1, and MFN2) are responsible for the majority of genetically diagnosed CMT. There are a substantial number of CMT patients where the genetic cause has not been identified. The most common forms of CMT are inherited in an autosomal dominant fashion. Dogs are also affected by a variety of peripheral neuropathies, which are generally breed-related, indicating a substantial genetic component. Our long-term goal is to develop an effective disease-modifying treatment for human CMT that could be used to block disease progression through testing drug candidates in a naturally occurring canine model. Therefore, the objective of this application is to determine the neuropathological features of canine acquired peripheral neuropathy (APN) and discover the genetic basis for the disease. The most prominent clinical feature of canine APN is laryngeal paralysis. APN is particularly common in the Labrador retriever. Many of the pathologic features of Labrador APN are similar to human peripheral neuropathy. The central hypothesis of this application is that canine APN will model an inherited human peripheral neuropathy. To accomplish the objective of this application we will pursue the following specific aims: 1) Determine neuropathological features of demyelination and axonal loss in dogs with a CMT- like APN and 2) Identify causal genetic variants that explain the CMT-like APN in the Labrador retriever. Under these aims, we will perform electro diagnostic testing, tissue biopsies, and whole genome single nucleotide polymorphism analysis of APN-affected cases and phenotype-negative controls. Causative variants will be identified through targeted re-sequencing of positional candidate regions of interest. The approach is innovative because it takes advantage of the high linkage disequilibrium within dog breeds to facilitate genetic mapping. Comprehensive understanding of the neuropathologic features and gene mutations associated with the APN trait is expected to enable development of a canine model for human peripheral neuropathy. Even if the causative mutation(s) are not associated with CMT-linked genes, this research may lead to the discovery of novel mutations associated with human peripheral nervous system disease.
Peripheral neuropathies are associated with a variety of conditions, such as aging and diabetes, and also constitute one of the most common forms of hereditary disease affecting the nervous system. There are currently no effective options for disease-modifying therapy. With the proposed investigation into the genetic basis of a breed-specific canine peripheral neuropathy, there is promise of a large animal treatment model and discovery of novel genetic risk factors. Such knowledge will drive identification of novel genetic markers for peripheral neuropathy that could be used for patient screening. Development of a large animal model of inherited peripheral neuropathy would help advance understanding of disease pathogenesis and development of novel treatments that have the potential to modify the course of inherited peripheral neuropathies in human patients.
