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Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44

The metabotropic glutamate receptor 1 (mGluR1) is abundantly expressed in the mammalian central nervous system, where it regulates intracellular calcium homeostasis in response to excitatory signaling. Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associat...

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Autores principales: Watson, Lauren M., Bamber, Elizabeth, Schnekenberg, Ricardo Parolin, Williams, Jonathan, Bettencourt, Conceição, Lickiss, Jennifer, Fawcett, Katherine, Clokie, Samuel, Wallis, Yvonne, Clouston, Penny, Sims, David, Houlden, Henry, Becker, Esther B.E., Németh, Andrea H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591020/
https://www.ncbi.nlm.nih.gov/pubmed/28886343
http://dx.doi.org/10.1016/j.ajhg.2017.08.005
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author Watson, Lauren M.
Bamber, Elizabeth
Schnekenberg, Ricardo Parolin
Williams, Jonathan
Bettencourt, Conceição
Lickiss, Jennifer
Fawcett, Katherine
Clokie, Samuel
Wallis, Yvonne
Clouston, Penny
Sims, David
Houlden, Henry
Becker, Esther B.E.
Németh, Andrea H.
author_facet Watson, Lauren M.
Bamber, Elizabeth
Schnekenberg, Ricardo Parolin
Williams, Jonathan
Bettencourt, Conceição
Lickiss, Jennifer
Fawcett, Katherine
Clokie, Samuel
Wallis, Yvonne
Clouston, Penny
Sims, David
Houlden, Henry
Becker, Esther B.E.
Németh, Andrea H.
author_sort Watson, Lauren M.
collection PubMed
description The metabotropic glutamate receptor 1 (mGluR1) is abundantly expressed in the mammalian central nervous system, where it regulates intracellular calcium homeostasis in response to excitatory signaling. Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-negative effect that is associated with juvenile-onset ataxia and intellectual disability. Crucially, the gain-of-function mutations could be pharmacologically modulated in vitro using an existing FDA-approved drug, Nitazoxanide, suggesting a possible avenue for treatment, which is currently unavailable for ataxias.
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spelling pubmed-55910202017-12-16 Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44 Watson, Lauren M. Bamber, Elizabeth Schnekenberg, Ricardo Parolin Williams, Jonathan Bettencourt, Conceição Lickiss, Jennifer Fawcett, Katherine Clokie, Samuel Wallis, Yvonne Clouston, Penny Sims, David Houlden, Henry Becker, Esther B.E. Németh, Andrea H. Am J Hum Genet Report The metabotropic glutamate receptor 1 (mGluR1) is abundantly expressed in the mammalian central nervous system, where it regulates intracellular calcium homeostasis in response to excitatory signaling. Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-negative effect that is associated with juvenile-onset ataxia and intellectual disability. Crucially, the gain-of-function mutations could be pharmacologically modulated in vitro using an existing FDA-approved drug, Nitazoxanide, suggesting a possible avenue for treatment, which is currently unavailable for ataxias. Elsevier 2017-09-07 2017-09-07 /pmc/articles/PMC5591020/ /pubmed/28886343 http://dx.doi.org/10.1016/j.ajhg.2017.08.005 Text en © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Report
Watson, Lauren M.
Bamber, Elizabeth
Schnekenberg, Ricardo Parolin
Williams, Jonathan
Bettencourt, Conceição
Lickiss, Jennifer
Fawcett, Katherine
Clokie, Samuel
Wallis, Yvonne
Clouston, Penny
Sims, David
Houlden, Henry
Becker, Esther B.E.
Németh, Andrea H.
Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44
title Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44
title_full Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44
title_fullStr Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44
title_full_unstemmed Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44
title_short Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44
title_sort dominant mutations in grm1 cause spinocerebellar ataxia type 44
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591020/
https://www.ncbi.nlm.nih.gov/pubmed/28886343
http://dx.doi.org/10.1016/j.ajhg.2017.08.005
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