title: Spectrin mutations cause spinocerebellar ataxia type 5.
abstract: We have discovered that beta-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. Beta-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 GluRdelta2 by protein blot and cell fractionation in SCA5 autopsy tissue. Cell culture studies demonstrate that wild-type but not mutant beta-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.
authors.affiliation: Department of Genetics, Cell Biology, and Development, University of Minnesota, 321 Church St. SE, Minneapolis, Minnesota 55455 USA.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Dick
authors.forename: Marcy R
authors.initials: MR
authors.lastname: Weatherspoon
authors.forename: Dan
authors.initials: D
authors.lastname: Gincel
authors.forename: Karen R
authors.initials: KR
authors.lastname: Armbrust
authors.forename: Joline C
authors.initials: JC
authors.lastname: Dalton
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dürr
authors.forename: Christine
authors.initials: C
authors.lastname: Zühlke
authors.forename: Katrin
authors.initials: K
authors.lastname: Bürk
authors.forename: H Brent
authors.initials: HB
authors.lastname: Clark
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Rothstein
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Schut
authors.forename: John W
authors.initials: JW
authors.lastname: Day
authors.forename: Laura P W
authors.initials: LP
authors.lastname: Ranum
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D002531:Cerebellum / Q000473:pathology; D002648:Child; D002874:Chromosome Mapping; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics*; D050581:Excitatory Amino Acid Transporter 4 / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D013049:Spectrin; D020754:Spinocerebellar Ataxias / Q000145:classification* / Q000235:genetics*
chemical_list: D027322:Amino Acid Transport System X-AG; D003598:Cytoskeletal Proteins; D050581:Excitatory Amino Acid Transporter 4; D009419:Nerve Tissue Proteins; C493391:SLC1A6 protein, human; C495133:SPTBN2 protein, human; C493390:Slc1a6 protein, mouse; D013049:Spectrin