THE SURVIVAL MOTOR-NEURON PROTEIN IN SPINAL MUSCULAR-ATROPHY

The 38 kDa survival motor neuron (SMN) protein is encoded by two ubiqu itously expressed genes: telomeric SMN (SMNT) and centromeric SMN (SMN C). Mutations in SMNT, but not SMNC, cause proximal spinal muscular at rophy (SMA), an autosomal recessive disorder that results in loss of m otor neurons, SMN is found in the cytoplasm and nucleus. The nuclear f orm is located in structures termed gems. Using a panel of anti-SMN an tibodies, we demonstrate that the SMN protein is expressed from both t he SMNT and SMNC genes. Western blot analysis of fibroblasts from SMA patients with various clinical severities of SMA showed a moderate red uction in the amount of SMN protein, particularly in type I (most seve re) patients. Immunocytochemical analysis of SMA patient fibroblasts i ndicates a significant reduction in the number of gems in type I SMA p atients and a correlation of the number of gems with clinical severity . This correlation to phenotype using primary fibroblasts may serve as a useful diagnostic tool in an easily accessible tissue. SMN is expre ssed at high levels in brain, kidney and liver, moderate levels in ske letal and cardiac muscle, and low levels in fibroblasts and lymphocyte s. In SMA patients, the SMN level was moderately reduced in muscle and lymphoblasts. In contrast, SMN was expressed at high levels in spinal cord from normals and non-SMA disease controls, but was reduced 100-f old in spinal cord from type I patients. The marked reduction of SMN i n type I SMA spinal cords is consistent with the features of this moto r neuron disease. We suggest that disruption of SMNT in type I patient s results in loss of SMN from motor neurons, resulting in the degenera tion of these neurons.