title: SMN oligomerization defect correlates with spinal muscular atrophy severity.
abstract: Spinal muscular atrophy (SMA) is a motor-neuron disorder resulting from anterior-horn-cell death. The autosomal recessive form has a carrier frequency of 1 in 50 and is the most common genetic cause of infant death. SMA is categorized as types I-III, ranging from severe to mild, based upon age of onset and clinical course. Two closely flanking copies of the survival motor neuron (SMN) gene are on chromosome 5q13 (ref. 1). The telomeric SMN (SMN1) copy is homozygously deleted or converted in >95% of SMA patients, while a small number of SMA disease alleles contain missense mutations within the carboxy terminus. We have identified a modular oligomerization domain within exon 6 of SMN1. All previously identified missense mutations map within or immediately adjacent to this domain. Comparison of wild-type to mutant SMN proteins of type I, II and III SMA patients showed a direct correlation between oligomerization and clinical type. Moreover, the most abundant centromeric SMN product, which encodes exons 1-6 but not 7, demonstrated reduced self-association. These findings identify decreased SMN self-association as a biochemical defect in SMA, and imply that disease severity is proportional to the intracellular concentration of oligomerization-competent SMN proteins.
authors.affiliation: Department of Dermatology, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Lorson
authors.forename: J
authors.initials: J
authors.lastname: Strasswimmer
authors.forename: J M
authors.initials: JM
authors.lastname: Yao
authors.forename: J D
authors.initials: JD
authors.lastname: Baleja
authors.forename: E
authors.initials: E
authors.lastname: Hahnen
authors.forename: B
authors.initials: B
authors.lastname: Wirth
authors.forename: T
authors.initials: T
authors.lastname: Le
authors.forename: A H
authors.initials: AH
authors.lastname: Burghes
authors.forename: E J
authors.initials: EJ
authors.lastname: Androphy
mesh_terms: D017362:Cyclic AMP Response Element-Binding Protein; D005982:Glutathione Transferase / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D055532:SMN Complex Proteins; D012720:Severity of Illness Index; D055533:Survival of Motor Neuron 1 Protein
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; D055533:Survival of Motor Neuron 1 Protein; D005982:Glutathione Transferase