FRAMESHIFT MUTATION IN THE SURVIVAL MOTOR-NEURON GENE IN A SEVERE CASE OF SMA TYPE-I

Recently, a spinal muscular atrophy (SMA) determining gene, termed sur vival motor neuron (SMN) gene, has been isolated from the 5q13 region and found deleted in most patients, A highly homologous copy of this g ene has also been isolated and located in a centromeric position, We h ave analyzed 158 patients (SMA types I-IV) and found deletions of SMN exon 7 in 96.8%, Mutations other than gross deletions seem to be extre mely rare, In one of the undeleted SMA type I patients, a newborn who survived for only 42 days, we detected a maternally inherited 5 bp mic rodeletion in exon 3, resulting in a premature stop codon, By RT-PCR a nd long range PCR amplification we were able to show that the deletion belongs to the SMN gene, rather than to the centromeric copy, and tha t the proposita had no paternal SMN gene, Analysis of the neuronal apo ptosis inhibitor protein (NAIP) gene, which maps close to SMN and has been proposed as a SMA modifying gene, suggests the presence of at lea st one full-length copy, Haplotype analysis of closely linked polymorp hic markers suggests that the proposita also lacks the maternally deri ved copy of the centromeric homologue of SMN supporting the hypothesis that the severity of the phenotype might depend on the reduced number of centromeric genes in addition to the frameshift mutation.