Increasing DNA marker informativeness in hereditary canine motor neuron disease

遗传性犬脊髓性肌萎缩症（HCSMA）是一种遗传性运动模型

Hereditary Canine Spinal Muscular Atrophy (HCSMA) is an inherited model of motor neuron disease (MND) that shares features with human MND and other neurodegenerative diseases. Weakness first appears in HCSMA because of decreased synaptic transmission at motor terminals. The disorder eventually manifests as motor unit failure and progresses to motor terminal degeneration, motor axon loss, and, at least in HCSMA heterozygotes, motor neuron loss. Evidence we have obtained recently demonstrates that motor neuron activity is a major contributing factor to the progression of HCSMA and that degeneration begins at the motor terminal. Although much is known about the pathology and cell biology of HCSMA, the identity of the defective gene remains unknown. Previous studies have shown that HCSMA is not caused by mutations in 2 of the most prominent genes (SOD1 and SMN) that cause familial MND in humans. This shows that identification of the defective gene in HCSMA will shed new light on mechanisms that cause the MND phenotype. Recent attempts to perform linkage analysis using a low resolution microsatellite marker set failed to establish significant linkage within the HCSMA colony. The main problem is that many of the microsatellite markers are not sufficiently polymorphic to yield significant linkage information. The likely cause of this is the extensive amount of inbreeding that has occurred in the HCSMA colony over the years. One solution to this problem would be to dramatically increase the number of markers. The recent publication of a canine SNP map and its commercial availability as a 64k microarray now make this approach feasible. We now propose to perform a linkage study on existing DNA from the HCSMA pedigree using these new resources as a first step towards identification of the defective gene in HCSMA.