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 survivalmotor neuron (SMN) gene, has been isolated from the 5q13 region and founddeleted in most patients. A highly homologous copy of this gene has alsobeen isolated and located in a centromeric position. We have analyzed 158patients (SMA types I-IV) and found deletions of SMN exon 7 in 96.8%.Mutations other than gross deletions seem to be extremely rare. In one ofthe undeleted SMA type I patients, a newborn who survived for only 42 days,we detected a maternally inherited 5 bp microdeletion in exon 3, resultingin a premature stop codon. By RT-PCR and long range PCR amplification wewere able to show that the deletion belongs to the SMN gene, rather than tothe centromeric copy, and that the proposita had no paternal SMN gene.Analysis of the neuronal apoptosis inhibitor protein (NAIP) gene, whichmaps close to SMN and has been proposed as a SMA modifying gene, suggeststhe presence of at least one full-length copy. Haplotype analysis ofclosely linked polymorphic markers suggests that the proposita also lacksthe maternally derived copy of the centromeric homologue of SMN supportingthe hypothesis that the severity of the phenotype might depend on thereduced number of centromeric genes in addition to the frameshift mutation.