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SMN oligomerization defect correlates with spinal muscular atrophy severity

Nature Genetics volume 19, pages 63–66 (1998)Cite this article

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 intracellu-lar concentration of oligomerization-competent SMN proteins.

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References

  1. Lefebvre, S. et al. Identification and characterization of a spinal muscular atrophy determining gene. Cell 80, 155–165 (1995).

    Article  CAS  Google Scholar 

  2. Brzustowicz, L.M. et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature 344, 540–541 (1990).

    Article  CAS  Google Scholar 

  3. Melki, J. et al. Gene for chronic spinal muscular atrophies maps to chromosome 5q. Nature 344, 767–768 (1990).

    Article  CAS  Google Scholar 

  4. Burghes, A. When is a deletion not a deletion?When it is converted. Am. J. Hum. Genet. 61, 9–15 (1997).

    Article  CAS  Google Scholar 

  5. Melki, J. Spinal muscular atrophy. Curr. Opin. Neurol. 10, 381–385 (1997).

    Article  CAS  Google Scholar 

  6. Bussaglia, E. et al. A frame-shift deletion in the survival motor neuron gene in Spanish spinal muscular atrophy patients. Nature Genet. 11, 335–337 (1995).

    Article  CAS  Google Scholar 

  7. Hahnen, E. et al. Molecular analysis of candidate genes on chromosome 5q13 in autosomal recessive spinal muscular atrophy: evidence of homozygous deletions of the SMN gene in unaffected individuals. Hum. Mol. Genet. 4, 1927–1933 (1995).

    Article  CAS  Google Scholar 

  8. Hahnen, E., Schonling, J., Rudnik-Schoneborn, S., Zerres, K. & Wirth, B. Hybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease. Am. J. Hum. Genet. 59, 1057–1065 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Rodrigues, N.R. et al. Deletions in the survival motor neuron gene on 5q13 in autosomal recessive spinal muscular atrophy. Hum. Mol. Genet. 4, 631–634 (1995).

    Article  CAS  Google Scholar 

  10. Brahe, C. et al. Frameshift mutation in the survival motor neuron gene in a severe case of SMA type I. Hum. Mol. Genet. 5, 1971–1976 (1996).

    Article  CAS  Google Scholar 

  11. Parsons, D.W. et al. An 11 base pair duplication in exon 6 of the SMN gene produces a type I spinal muscular atrophy (SMA) phenotype: further evidence for SMN as the primary SMA-determining gene. Hum. Mol. Genet. 5, 1727–1732 (1996).

    Article  CAS  Google Scholar 

  12. van der Steege, G. et al. Apparent gene conversions involving the SMN gene in the region of the spinal muscular atrophy locus on chromosome 5. Am. J. Hum. Genet. 59, 834–838 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Velasco, E., Valero, C., Valero, A., Moreno, F. & Hernandez-Chico, C. Molecular analysis of the SMN and NAIP genes in Spanish spinal muscular atrophy (SMA) families and correlation between number of copies of CBCD541 and SMA phenotype. Hum. Mol. Genet. 5, 257–263 (1996).

    Article  CAS  Google Scholar 

  14. Campbell, L., Potter, A., Ignatius, J., Dubowitz, V. & Davies, K. Genomic variation and gene conversion in spinal muscular atrophy: implications for disease process and clinical phenotype. Am. J. Hum. Genet. 61, 40–50 (1997).

    Article  CAS  Google Scholar 

  15. DiDonato, C.J. et al. Deletion and conversion in spinal muscular atrophy patients: is there a relationship to severity? Ann Neurol. 41, 230–237 (1997).

    Article  CAS  Google Scholar 

  16. McAndrew, P.E. et al. Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number. Am. J. Hum. Genet. 60, 1411–1422 (1997).

    Article  CAS  Google Scholar 

  17. Hahnen, E. et al. Missense mutations in exon 6 of the survival motor neuron gene in patients with spinal muscular atrophy. Hum. Mol. Genet. 6, 821–825 (1997).

    Article  CAS  Google Scholar 

  18. Talbot, K. et al. Missense mutation clustering in the survival motor neuron gene: a role for a conserved tyrosine and glycine rich region of the protein in RNA metabolism? Hum. Mol. Genet. 6, 497–500 (1997).

    Article  CAS  Google Scholar 

  19. Gennarelli, M. et al. Survival motor neuron gene transcript analysis in muscles from spinal muscular atrophy patients. Biochem. Biophys. Res. Commun. 213, 342–348 (1995).

    Article  CAS  Google Scholar 

  20. Lefebvre, S. et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nature Genet. 16, 265–269 (1997).

    Article  CAS  Google Scholar 

  21. Coovert, D. et al. The survival motor neuron protein in spinal muscular atrophy. Hum. Mol. Gen. 6, 1205–1214 (1997).

    Article  CAS  Google Scholar 

  22. Liu, Q., Fischer, U., Wang, F. & Dreyfuss, G. The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins. Cell 90, 1013–1021 (1997).

    Article  CAS  Google Scholar 

  23. Schrank, B. et al. Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. Proc. Natl. Acad. Sci. USA 94, 9920–9925 (1997).

    Article  CAS  Google Scholar 

  24. Breiding, D.E., Grossel, M.J. & Androphy, E.J. Genetic analysis of the bovine papillomavirus E2 transcriptional activation domain. Virology 221, 34–43 (1996).

    Article  CAS  Google Scholar 

  25. Chen, J.J., Reid, C.E., Band, V. & Androphy, E.J. Interaction of papillomavirus E6 oncoproteins with a putative calcium-binding protein. Science 269, 529–531 (1995).

    Article  CAS  Google Scholar 

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Author notes

  1. Christian L. Lorson and John Strasswimmer: C.L.L. & J.S contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts, 02111, USA

    Christian L. Lorson, Jun-Mei Yao & Elliot J. Androphy

  2. Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA

    John Strasswimmer & Elliot J. Androphy

  3. Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts, USA

    James D. Baleja

  4. Institute of Human Genetics, University of Bonn, Bonn, Germany

    Eric Hahnen & Brunhilde Wirth

  5. Departments of Neurology, Medical Biochemistry and Molecular Genetics, Ohio State University, USA

    Thanh Le & Arthur H.M. Burghes

Authors
  1. Christian L. Lorson
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  2. John Strasswimmer
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  7. Thanh Le
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  8. Arthur H.M. Burghes
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  9. Elliot J. Androphy
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Correspondence to Elliot J. Androphy.

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Lorson, C., Strasswimmer, J., Yao, JM. et al. SMN oligomerization defect correlates with spinal muscular atrophy severity. Nat Genet 19, 63–66 (1998). https://doi.org/10.1038/ng0598-63

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