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.
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We would like to thank family members for their participation, L.F. Schut, J. Wayne and D. Bary for help with clinics, H. Orr for critically reading our manuscript and contributing the B05 mice, J. Brennan for help with trafficking analysis, E. Denis for technical assistance and Kazusa DNA Research Institute for the spectrin cDNA clone KIAA0302. We also thank E. Rubin, C. Pearson, L. Lanier, S. Conner, L. Chen and T. Hays for helpful discussions. We acknowledge funding from the Programme Hospitalier de Recherche Clinique (A.D.), the Verum Foundation (A.B.), the European Community (European Integrated Project on Spinocerebellar Ataxias (EUROSCA)) (A.B.), the National Ataxia Foundation (Y.I., J.W.D. and L.P.W.R.), the Bob Allison Ataxia Research Center (L.P.W.R.), the Minnesota Medical Foundation (J.W.D.) and the US National Institutes of Health (J.D.R. and L.P.W.R.).