The survival motor neuron protein in spinal muscular atrophy

The 38 kDa survival motor neuron (SMN) protein is encoded by twoubiquitously expressed genes: telomeric SMN (SMN(T)) and centromeric SMN(SMN(C)). Mutations in SMN(T), but not SMN(C), cause proximal spinalmuscular atrophy (SMA), an autosomal recessive disorder that results inloss of motor neurons. SMN is found in the cytoplasm and nucleus. Thenuclear form is located in structures termed gems. Using a panel ofanti-SMN antibodies, we demonstrate that the SMN protein is expressed fromboth the SMN(T) and SMN(C) genes. Western blot analysis of fibroblasts fromSMA patients with various clinical severities of SMA showed a moderatereduction in the amount of SMN protein, particularly in type I (mostsevere) patients. Immunocytochemical analysis of SMA patient fibroblastsindicates a significant reduction in the number of gems in type I SMApatients and a correlation of the number of gems with clinical severity.This correlation to phenotype using primary fibroblasts may serve as auseful diagnostic tool in an easily accessible tissue. SMN is expressed athigh levels in brain, kidney and liver, moderate levels in skeletal andcardiac muscle, and low levels in fibroblasts and lymphocytes. In SMApatients, the SMN level was moderately reduced in muscle and lymphoblasts.In contrast, SMN was expressed at high levels in spinal cord from normalsand non- SMA disease controls, but was reduced 100-fold in spinal cord fromtype I patients. The marked reduction of SMN in type I SMA spinal cords isconsistent with the features of this motor neuron disease. We suggest thatdisruption of SMN(T) in type I patients results in loss of SMN from motorneurons, resulting in the degeneration of these neurons.