Spectrin mutations cause spinocerebellar ataxia type 5

• Published in: Nature genetics Vol. 38; no. 2; pp. 184 - 190
• Main Authors: Ranum, Laura P W, Ikeda, Yoshio, Dick, Katherine A, Weatherspoon, Marcy R, Gincel, Dan, Armbrust, Karen R, Dalton, Joline C, Stevanin, Giovanni, Dürr, Alexandra, Zühlke, Christine, Bürk, Katrin, Clark, H Brent, Brice, Alexis, Rothstein, Jeffrey D, Schut, Lawrence J, Day, John W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.02.2006
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Amino Acid Sequence; Amino Acid Transport System X-AG - metabolism; Animals; Biological and medical sciences; Case-Control Studies; Cell culture; Cell Line; Cerebellum - pathology; Child; Chromosome Mapping; Complications and side effects; Cytoskeletal Proteins - chemistry; Cytoskeletal Proteins - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diagnosis; Excitatory Amino Acid Transporter 4 - metabolism; Female; Fractionation; Fundamental and applied biological sciences. Psychology; Gene expression; Gene mutations; Genetic aspects; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Heredity; Humans; Male; Medical sciences; Membranes; Mice; Middle Aged; Molecular Sequence Data; Mutation; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - genetics; Nervous system; Neurology; Pedigree; Proteins; Risk factors; Spectrin; Spinocerebellar ataxia; Spinocerebellar Ataxias - classification; Spinocerebellar Ataxias - genetics; United States; Spectrin; Nervous system diseases; Spinocerebellar ataxia; Central nervous system disease; Degenerative disease; Mutation; Genetic disease
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1728

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.