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Spectrin mutations cause spinocerebellar ataxia type 5

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.

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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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References

  1. Schols, L., Bauer, P., Schmidt, T., Schulte, T. & Riess, O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol. 3, 291–304 (2004).

    Article  Google Scholar 

  2. Ranum, L.P.W., Schut, L.J., Lundgren, J.K., Orr, H.T. & Livingston, D.M. Spinocerebellar ataxia gene type 5 in a family descended from the paternal grandparents of President Lincoln maps to chromosome 11. Nat. Genet. 8, 280–284 (1994).

    Article  CAS  Google Scholar 

  3. Liquori, C.L., Schut, L.J., Clark, H.B., Day, J.W. & Ranum, L.P.W. Spinocerebellar ataxia type 5. in The Cerebellum and Its Disorders (eds. Manto, M.U. & Pandolfo, M.) 445–450 (Cambridge Univ. Press, Cambridge, 2002).

    Google Scholar 

  4. Stevanin, G., Herman, A., Brice, A. & Durr, A. Clinical and MRI findings in spinocerebellar ataxia type 5. Neurology 53, 1355–1357 (1999).

    Article  CAS  Google Scholar 

  5. Burk, K. et al. Spinocerebellar ataxia type 5: clinical and molecular genetic features of a German kindred. Neurology 62, 327–329 (2004).

    Article  CAS  Google Scholar 

  6. Ohara, O., Ohara, R., Yamakawa, H., Nakajima, D. & Nakayama, M. Characterization of a new beta-spectrin gene which is predominantly expressed in brain. Brain Res. Mol. Brain Res. 57, 181–192 (1998).

    Article  CAS  Google Scholar 

  7. Stankewich, M.C. et al. A widely expressed betaIII spectrin associated with Golgi and cytoplasmic vesicles. Proc. Natl. Acad. Sci. USA 95, 14158–14163 (1998).

    Article  CAS  Google Scholar 

  8. Holleran, E.A. et al. beta III spectrin binds to the Arp1 subunit of dynactin. J. Biol. Chem. 276, 36598–36605 (2001).

    Article  CAS  Google Scholar 

  9. Parkinson, N.J. et al. Mutant beta-spectrin 4 causes auditory and motor neuropathies in quivering mice. Nat. Genet. 29, 61–65 (2001).

    Article  CAS  Google Scholar 

  10. Jackson, M. et al. Modulation of the neuronal glutamate transporter EAAT4 by two interacting proteins. Nature 410, 89–93 (2001).

    Article  CAS  Google Scholar 

  11. Lin, X., Antalffy, B., Kang, D., Orr, H.T. & Zoghbi, H.Y. Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat. Neurosci. 3, 157–163 (2000).

    Article  CAS  Google Scholar 

  12. Serra, H.G. et al. Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum. Mol. Genet. 13, 2535–2543 (2004).

    Article  CAS  Google Scholar 

  13. Welsh, J.P. et al. Why do Purkinje cells die so easily after global brain ischemia? Aldolase C, EAAT4, and the cerebellar contribution to posthypoxic myoclonus. Adv. Neurol. 89, 331–359 (2002).

    Google Scholar 

  14. Raiteri, L., Raiteri, M. & Bonanno, G. Coexistence and function of different neurotransmitter transporters in the plasma membrane of CNS neurons. Prog. Neurobiol. 68, 287–309 (2002).

    Article  CAS  Google Scholar 

  15. Lalouette, A., Guenet, J.L. & Vriz, S. Hotfoot mouse mutations affect the delta 2 glutamate receptor gene and are allelic to lurcher. Genomics 50, 9–13 (1998).

    Article  CAS  Google Scholar 

  16. Zuo, J. et al. Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene. Nature 388, 769–773 (1997).

    Article  CAS  Google Scholar 

  17. Puls, I. et al. Mutant dynactin in motor neuron disease. Nat. Genet. 33, 455–456 (2003).

    Article  CAS  Google Scholar 

  18. Hafezparast, M. et al. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300, 808–812 (2003).

    Article  CAS  Google Scholar 

  19. Gauthier, L.R. et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118, 127–138 (2004).

    Article  CAS  Google Scholar 

  20. Stokin, G.B. et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science 307, 1282–1288 (2005).

    Article  CAS  Google Scholar 

  21. Knight, M.A. et al. Dominantly inherited ataxia and dysphonia with dentate calcification: spinocerebellar ataxia type 20. Brain 127, 1172–1181 (2004).

    Article  Google Scholar 

  22. Worth, P.F. et al. Autosomal dominant cerebellar ataxia type III: linkage in a large British family to a 7.6-cM region on chromosome 15q14–21.3. Am. J. Hum. Genet. 65, 420–426 (1999).

    Article  CAS  Google Scholar 

  23. Stevanin, G. et al. Spinocerebellar ataxia with sensory neuropathy (SCA25) maps to chromosome 2p. Ann. Neurol. 55, 97–104 (2004).

    Article  CAS  Google Scholar 

  24. Park, E.C. & Horvitz, H.R. Mutations with dominant effects on the behavior and morphology of the nematode Caenorhabditis elegans. Genetics 113, 821–852 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Gold, D.A. et al. RORalpha coordinates reciprocal signaling in cerebellar development through sonic hedgehog and calcium-dependent pathways. Neuron 40, 1119–1131 (2003).

    Article  CAS  Google Scholar 

  26. McKusick, V.A. The defect in Marfan syndrome. Nature 352, 279–281 (1991).

    Article  CAS  Google Scholar 

  27. Papadopoulos, N., Leach, F.S., Kinzler, K.W. & Vogelstein, B. Monoallelic mutation analysis (MAMA) for identifying germline mutations. Nat. Genet. 11, 99–102 (1995).

    Article  CAS  Google Scholar 

  28. Gordon, D., Abajian, C. & Green, P. Consed: a graphical tool for sequence finishing. Genome Res. 8, 195–202 (1998).

    Article  CAS  Google Scholar 

  29. Lee, S.H., Valtschanoff, J.G., Kharazia, V.N., Weinberg, R. & Sheng, M. Biochemical and morphological characterization of an intracellular membrane compartment containing AMPA receptors. Neuropharmacology 41, 680–692 (2001).

    Article  CAS  Google Scholar 

  30. Krawczak, M. & Cooper, D.N. Gene deletions causing human genetic disease: mechanisms of mutagenesis and the role of the local DNA sequence environment. Hum. Genet. 86, 425–441 (1991).

    Article  CAS  Google Scholar 

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Acknowledgements

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). https://doi.org/10.1038/ng1728

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