Spectrin mutations cause spinocerebellar ataxia type 5

Yoshio Ikeda; Katherine A. Dick; Marcy R. Weatherspoon; Dan Gincel; Karen R. Armbrust; Joline C. Dalton; Giovanni Stevanin; Alexandra Dürr; Christine Zühlke; Katrin Bürk; H. Brent Clark; Alexis Brice; Jeffrey D. Rothstein; Lawrence J. Schut; John W. Day; Laura P.W. Ranum

doi:10.1038/ng1728

Spectrin mutations cause spinocerebellar ataxia type 5

Yoshio Ikeda, Katherine A. Dick, Marcy R. Weatherspoon, Dan Gincel, Karen R. Armbrust, Joline C. Dalton, Giovanni Stevanin, Alexandra Dürr, Christine Zühlke, Katrin Bürk, H. Brent Clark, Alexis Brice, Jeffrey D. Rothstein, Lawrence J. Schut, John W. Day, Laura P.W. Ranum^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Humangenetik

260 Zitate (Scopus)

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.

Originalsprache	Englisch
Zeitschrift	Nature Genetics
Jahrgang	38
Ausgabenummer	2
Seiten (von - bis)	184-190
Seitenumfang	7
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng1728
Publikationsstatus	Veröffentlicht - 02.2006

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Querschnittsbereich: Medizinische Genetik

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10.1038/ng1728

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@article{33a74a7ff2b34545add16404ee476a44,

title = "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.",

author = "Yoshio Ikeda and Dick, {Katherine A.} and Weatherspoon, {Marcy R.} and Dan Gincel and Armbrust, {Karen R.} and Dalton, {Joline C.} and Giovanni Stevanin and Alexandra D{\"u}rr and Christine Z{\"u}hlke and Katrin B{\"u}rk and Clark, {H. Brent} and Alexis Brice and Rothstein, {Jeffrey D.} and Schut, {Lawrence J.} and Day, {John W.} and Ranum, {Laura P.W.}",

note = "Funding Information: 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.).",

year = "2006",

month = feb,

doi = "10.1038/ng1728",

language = "English",

volume = "38",

pages = "184--190",

journal = "Nature Genetics",

issn = "1061-4036",

number = "2",

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TY - JOUR

T1 - Spectrin mutations cause spinocerebellar ataxia type 5

AU - Ikeda, Yoshio

AU - Dick, Katherine A.

AU - Weatherspoon, Marcy R.

AU - Gincel, Dan

AU - Armbrust, Karen R.

AU - Dalton, Joline C.

AU - Stevanin, Giovanni

AU - Dürr, Alexandra

AU - Zühlke, Christine

AU - Bürk, Katrin

AU - Clark, H. Brent

AU - Brice, Alexis

AU - Rothstein, Jeffrey D.

AU - Schut, Lawrence J.

AU - Day, John W.

AU - Ranum, Laura P.W.

N1 - Funding Information: 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.).

PY - 2006/2

Y1 - 2006/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=31744441984&partnerID=8YFLogxK

U2 - 10.1038/ng1728

DO - 10.1038/ng1728

M3 - Journal articles

C2 - 16429157

AN - SCOPUS:31744441984

SN - 1061-4036

VL - 38

SP - 184

EP - 190

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

Spectrin mutations cause spinocerebellar ataxia type 5

Abstract

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