Nature Genetics 38, 184 - 190 (2006)
Published online: 22 January 2006; | doi:10.1038/ng1728
Spectrin mutations cause spinocerebellar ataxia type 5Yoshio Ikeda1, 2, 10, Katherine A Dick1, 2, 10, Marcy R Weatherspoon1, 2, Dan Gincel5, Karen R Armbrust1, 2, Joline C Dalton1, 2, Giovanni Stevanin6, Alexandra Dürr6, Christine Zühlke7, Katrin Bürk8, H Brent Clark3, 4, Alexis Brice6, Jeffrey D Rothstein5, Lawrence J Schut9, John W Day2, 4
& Laura P W Ranum1, 21
Department of Genetics, Cell Biology, and Development, University of Minnesota, 321 Church St. SE, Minneapolis, Minnesota 55455 USA. 2
Institute of Human Genetics, University of Minnesota, 420 Delaware St. SE, Minneapolis, Minnesota 55455, USA. 3
Department of Laboratory Medicine and Pathology, University of Minnesota, 420 Delaware St. SE, Minneapolis, Minnesota 55455, USA. 4
Department of Neurology, University of Minnesota, 516 Delaware St. SE, Minneapolis, Minnesota 55455, USA. 5
Department of Neurology and Neuroscience, Johns Hopkins University, 600 N. Wolfe St., Baltimore, Maryland, 21287 USA. 6
UMR679 INSERM/Paris-VI University and Department of Genetics Cytogenetics and Embryology, AP-HP, Hôpital de la Salpêtrière, 47 Boulevard de l' Hôpital, 75013 Paris, France. 7
Institute of Human Genetics, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany. 8
Department of Neurology and Institute of Brain Research, University of Tübingen, Calwerstr. 3, D-72076 Tübingen, Germany. 9
Centra-Care Clinic, 1200 Sixth Avenue North, St. Cloud, Minnesota 56303, USA. 10
These authors contributed equally to this work.
Correspondence should be addressed to Laura P W Ranum ranum001@umn.edu We have discovered that  -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. -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 GluR 2 by protein blot and cell fractionation in SCA5 autopsy tissue. Cell culture studies demonstrate that wild-type but not mutant -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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