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SMN oligomerization defect correlates with spinal muscular atrophy severity.
- Source :
-
Nature genetics [Nat Genet] 1998 May; Vol. 19 (1), pp. 63-6. - Publication Year :
- 1998
-
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.
- Subjects :
- Cyclic AMP Response Element-Binding Protein
Glutathione Transferase genetics
HeLa Cells
Humans
Muscular Atrophy, Spinal physiopathology
Nerve Tissue Proteins metabolism
RNA-Binding Proteins
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins metabolism
SMN Complex Proteins
Severity of Illness Index
Survival of Motor Neuron 1 Protein
Muscular Atrophy, Spinal genetics
Mutation
Nerve Tissue Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1061-4036
- Volume :
- 19
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature genetics
- Publication Type :
- Academic Journal
- Accession number :
- 9590291
- Full Text :
- https://doi.org/10.1038/ng0598-63