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Spectrin mutations cause spinocerebellar ataxia type 5


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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Figure 1: Pedigree of the Lincoln SCA5 family.
Figure 2: Mapping and cloning SCA5 mutations.
Figure 3: The three SCA5 mutations and β-III spectrin expression.
Figure 4: Protein blots, immunohistochemistry and TIRF microscopy demonstrate effects of mutant β-III spectrin on EAAT4.

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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.).

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Correspondence to Laura P W Ranum.

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Supplementary information

Supplementary Figure 1

Subcellular distribution of EAAT4 and GluRδ2. (PDF 1722 kb)

Supplementary Table 1

Summary of DNA sequence variations of exons found in 3 BAC regions. (PDF 91 kb)

Supplementary Table 2

Primer sequences and PCR conditions. (PDF 101 kb)

Supplementary Video 1

Lateral trafficking of eGFP-EAAT4 in HEK293 cells. (MOV 744 kb)

Supplementary Video 2

Lateral trafficking of eGFP-EAAT4 in HEK293 cells co-transfected with wildtype β-III spectrin. (MOV 117 kb)

Supplementary Video 3

Lateral trafficking of eGFP-EAAT4 in HEK293 cells co-transfected with the mutant β-III spectrin. (MOV 317 kb)

Supplementary Video 4

Lateral trafficking of eGFP-EAAT3 in HEK293 cells. (MOV 291 kb)

Supplementary Video 5

Lateral trafficking of eGFP-EAAT3 in HEK293 cells co-transfected with wildtype β-III spectrin. (MOV 187 kb)

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Ikeda, Y., Dick, K., Weatherspoon, M. et al. Spectrin mutations cause spinocerebellar ataxia type 5. Nat Genet 38, 184–190 (2006).

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