SMN oligomerization defect correlates with spinal muscular atrophy severity

Christian L. Lorson, John Strasswimmer, Jun Mei Yao, James D. Baleja, Eric Hahnen, Brunhilde Wirth, Thanh Le, Arthur H M Burghes, Elliot Androphy

Research output: Contribution to journalArticle

376 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)63-66
Number of pages4
JournalNature Genetics
Volume19
Issue number1
DOIs
StatePublished - 1998
Externally publishedYes

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Spinal Muscular Atrophy
Motor Neurons
Spinal Muscular Atrophies of Childhood
Missense Mutation
Exons
Anterior Horn Cells
Muscular Diseases
Age of Onset
Cause of Death
Proteins
Cell Death
Chromosomes
Alleles
Genes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Lorson, C. L., Strasswimmer, J., Yao, J. M., Baleja, J. D., Hahnen, E., Wirth, B., ... Androphy, E. (1998). SMN oligomerization defect correlates with spinal muscular atrophy severity. Nature Genetics, 19(1), 63-66. https://doi.org/10.1038/ng0598-63

SMN oligomerization defect correlates with spinal muscular atrophy severity. / Lorson, Christian L.; Strasswimmer, John; Yao, Jun Mei; Baleja, James D.; Hahnen, Eric; Wirth, Brunhilde; Le, Thanh; Burghes, Arthur H M; Androphy, Elliot.

In: Nature Genetics, Vol. 19, No. 1, 1998, p. 63-66.

Research output: Contribution to journalArticle

Lorson, CL, Strasswimmer, J, Yao, JM, Baleja, JD, Hahnen, E, Wirth, B, Le, T, Burghes, AHM & Androphy, E 1998, 'SMN oligomerization defect correlates with spinal muscular atrophy severity', Nature Genetics, vol. 19, no. 1, pp. 63-66. https://doi.org/10.1038/ng0598-63
Lorson CL, Strasswimmer J, Yao JM, Baleja JD, Hahnen E, Wirth B et al. SMN oligomerization defect correlates with spinal muscular atrophy severity. Nature Genetics. 1998;19(1):63-66. https://doi.org/10.1038/ng0598-63
Lorson, Christian L. ; Strasswimmer, John ; Yao, Jun Mei ; Baleja, James D. ; Hahnen, Eric ; Wirth, Brunhilde ; Le, Thanh ; Burghes, Arthur H M ; Androphy, Elliot. / SMN oligomerization defect correlates with spinal muscular atrophy severity. In: Nature Genetics. 1998 ; Vol. 19, No. 1. pp. 63-66.
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