Spectrin mutations cause spinocerebellar ataxia type 5

Yoshio Ikeda, Katherine A. Dick, Marcy R. Weatherspoon, Dan Gincel, Karen R. Armbrust, Joline C. Dalton, Giovanni Stevanin, Alexandra Dürr, Christine Zühlke, Katrin Bürk, H. Brent Clark, Alexis Brice, Jeffrey D. Rothstein, Lawrence J. Schut, John W. Day, Laura P.W. Ranum

Research output: Contribution to journalArticle

Abstract

We have discovered that β-III spectrin (SPTBN2) mutations cause spinocerebellar ataxia type 5 (SCA5) in an 11-generation American kindred descended from President Lincoln's grandparents and two additional families. Two families have separate in-frame deletions of 39 and 15 bp, and a third family has a mutation in the actin/ARP1 binding region, β-III spectrin is highly expressed in Purkinje cells and has been shown to stabilize the glutamate transporter EAAT4 at the surface of the plasma membrane. We found marked differences in EAAT4 and GluRδ2 by protein blot and cell fractionation in SCA5 autopsy tissue. Cell culture studies demonstrate that wild-type but not mutant β-III spectrin stabilizes EAAT4 at the plasma membrane. Spectrin mutations are a previously unknown cause of ataxia and neurodegenerative disease that affect membrane proteins involved in glutamate signaling.

Original languageEnglish (US)
Pages (from-to)184-190
Number of pages7
JournalNature genetics
Volume38
Issue number2
DOIs
StatePublished - Feb 2006

ASJC Scopus subject areas

  • Genetics

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    Ikeda, Y., Dick, K. A., Weatherspoon, M. R., Gincel, D., Armbrust, K. R., Dalton, J. C., Stevanin, G., Dürr, A., Zühlke, C., Bürk, K., Clark, H. B., Brice, A., Rothstein, J. D., Schut, L. J., Day, J. W., & Ranum, L. P. W. (2006). Spectrin mutations cause spinocerebellar ataxia type 5. Nature genetics, 38(2), 184-190. https://doi.org/10.1038/ng1728