MOLECULAR PATHOGENESIS OF FELINE SPINAL MUSCULAR ATROPHY

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Inherited defects causing abnormal development or degeneration of the central nervous system comprise a large proportion of fetal and childhood mortality and morbidity. There are many forms of spinal muscular atrophy (SMA) in humans, but for only a few has the molecular basis been established. The common form of autosomal recessive, early-onset SMA is attributed to defects in the region of the survival motor neuron gene (SMN) locus on chromosome 5q12-q14 and is a leading cause of infant mortality. With an incidence of approximately 1:10,000 births, the severe form of 5q SMA is the most common autosomal recessive disease lethal to infants, and when including milder forms, it is the second most common pediatric neuromuscular disorder overall. We have identified a domestic cat family exhibiting an autosomal recessive form of SMA caused by loss of spinal cord motor neurons and resulting in early juvenile-onset skeletal muscle atrophy, weakness, and loss of function. The feline disorder is clinically-distinguishable from SMA type III in humans and represents a new and unique animal model of human SMA. The long-term goals of this investigation are to characterize and use this feline model to better understand normal motor neuron development, maintenance and function, with the objective of developing novel therapeutics for spinal muscular atrophy in humans. Characterization of this animal model will address the need to better understand the mechanisms of motor neuron disease in humans and, potentially, provide a system in which to test new therapeutic protocols. Immediately we proposed to make a detailed description of the pathology of the disorder and to determine the molecular genetic basis of feline SMA. The specific aims of this proposal are: 1) to establish and maintain a breeding colony of SMA cats and to perform matings which will be most informative for genetic linkage studies and will produce additional affected and littermate controls for studies of pathogenesis, 2) to characterize the histopathology of feline SMA as the disorder progresses from late gestation through onset of clinical signs, 3) to determine the molecular basis of feline SMA by examining candidate genes for evidence to the feline SMA disease locus. Initial candidate genes will be those implicated in human SMA, but otherwise a comparative positional-candidate gene approach will be taken.