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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2017
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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. |
format | Online Article Text |
id | pubmed-5591020 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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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