title: Homozygous SMN1 deletions in unaffected family members and modification of the phenotype by SMN2.
abstract: Spinal muscular atrophy is a common autosomal recessive neuromuscular disorder caused by the homozygous loss of the SMN1 gene. The absence of the SMN1 gene has been shown to occur in all types of SMA, childhood and adult forms. In rare cases, asymptomatic family members have also been found with homozygous mutations in the SMN1 gene, suggesting a role for phenotypic modifiers. We describe three unrelated asymptomatic individuals, with family histories of SMA, who were shown to have the homozygous SMN1 deletion. Quantitative studies indicated that the three individuals all had increased SMN2 copy numbers. These cases not only support the role of SMN2 in modifying the phenotype, but our data also demonstrate that expression levels consistent with five copies of the SMN2 genes maybe enough to compensate for the absence of the SMN1 gene. Lastly, in cases similar to the ones described, the measurement of the SMN2 gene copy number may provide valuable prognostic information.
authors.affiliation: Department of Pathology, Ohio State University, Columbus, Ohio 43210, USA. prior-1@medctr.osu.edu
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Prior
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Swoboda
authors.forename: H Denman
authors.initials: HD
authors.lastname: Scott
authors.forename: Ashley Q
authors.initials: AQ
authors.lastname: Hejmanowski
mesh_terms: D000328:Adult; D002675:Child, Preschool; D017362:Cyclic AMP Response Element-Binding Protein; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D008297:Male; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; D014897:Spinal Muscular Atrophies of Childhood / Q000235:genetics* / Q000473:pathology; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein