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Deletion at ITPR1 Underlies Ataxia in Mice and Spinocerebellar Ataxia 15 in Humans
We observed a severe autosomal recessive movement disorder in mice used within our laboratory. We pursued a series of experiments to define the genetic lesion underlying this disorder and to identify a cognate disease in humans with mutation at the same locus. Through linkage and sequence analysis w...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2007
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1892049/ https://www.ncbi.nlm.nih.gov/pubmed/17590087 http://dx.doi.org/10.1371/journal.pgen.0030108 |
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author | van de Leemput, Joyce Chandran, Jayanth Knight, Melanie A Holtzclaw, Lynne A Scholz, Sonja Cookson, Mark R Houlden, Henry Gwinn-Hardy, Katrina Fung, Hon-Chung Lin, Xian Hernandez, Dena Simon-Sanchez, Javier Wood, Nick W Giunti, Paola Rafferty, Ian Hardy, John Storey, Elsdon Gardner, R. J. McKinlay Forrest, Susan M Fisher, Elizabeth M. C Russell, James T Cai, Huaibin Singleton, Andrew B |
author_facet | van de Leemput, Joyce Chandran, Jayanth Knight, Melanie A Holtzclaw, Lynne A Scholz, Sonja Cookson, Mark R Houlden, Henry Gwinn-Hardy, Katrina Fung, Hon-Chung Lin, Xian Hernandez, Dena Simon-Sanchez, Javier Wood, Nick W Giunti, Paola Rafferty, Ian Hardy, John Storey, Elsdon Gardner, R. J. McKinlay Forrest, Susan M Fisher, Elizabeth M. C Russell, James T Cai, Huaibin Singleton, Andrew B |
author_sort | van de Leemput, Joyce |
collection | PubMed |
description | We observed a severe autosomal recessive movement disorder in mice used within our laboratory. We pursued a series of experiments to define the genetic lesion underlying this disorder and to identify a cognate disease in humans with mutation at the same locus. Through linkage and sequence analysis we show here that this disorder is caused by a homozygous in-frame 18-bp deletion in Itpr1 (Itpr1(Δ18/Δ18)), encoding inositol 1,4,5-triphosphate receptor 1. A previously reported spontaneous Itpr1 mutation in mice causes a phenotype identical to that observed here. In both models in-frame deletion within Itpr1 leads to a decrease in the normally high level of Itpr1 expression in cerebellar Purkinje cells. Spinocerebellar ataxia 15 (SCA15), a human autosomal dominant disorder, maps to the genomic region containing ITPR1; however, to date no causal mutations had been identified. Because ataxia is a prominent feature in Itpr1 mutant mice, we performed a series of experiments to test the hypothesis that mutation at ITPR1 may be the cause of SCA15. We show here that heterozygous deletion of the 5′ part of the ITPR1 gene, encompassing exons 1–10, 1–40, and 1–44 in three studied families, underlies SCA15 in humans. |
format | Text |
id | pubmed-1892049 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-18920492007-06-30 Deletion at ITPR1 Underlies Ataxia in Mice and Spinocerebellar Ataxia 15 in Humans van de Leemput, Joyce Chandran, Jayanth Knight, Melanie A Holtzclaw, Lynne A Scholz, Sonja Cookson, Mark R Houlden, Henry Gwinn-Hardy, Katrina Fung, Hon-Chung Lin, Xian Hernandez, Dena Simon-Sanchez, Javier Wood, Nick W Giunti, Paola Rafferty, Ian Hardy, John Storey, Elsdon Gardner, R. J. McKinlay Forrest, Susan M Fisher, Elizabeth M. C Russell, James T Cai, Huaibin Singleton, Andrew B PLoS Genet Research Article We observed a severe autosomal recessive movement disorder in mice used within our laboratory. We pursued a series of experiments to define the genetic lesion underlying this disorder and to identify a cognate disease in humans with mutation at the same locus. Through linkage and sequence analysis we show here that this disorder is caused by a homozygous in-frame 18-bp deletion in Itpr1 (Itpr1(Δ18/Δ18)), encoding inositol 1,4,5-triphosphate receptor 1. A previously reported spontaneous Itpr1 mutation in mice causes a phenotype identical to that observed here. In both models in-frame deletion within Itpr1 leads to a decrease in the normally high level of Itpr1 expression in cerebellar Purkinje cells. Spinocerebellar ataxia 15 (SCA15), a human autosomal dominant disorder, maps to the genomic region containing ITPR1; however, to date no causal mutations had been identified. Because ataxia is a prominent feature in Itpr1 mutant mice, we performed a series of experiments to test the hypothesis that mutation at ITPR1 may be the cause of SCA15. We show here that heterozygous deletion of the 5′ part of the ITPR1 gene, encompassing exons 1–10, 1–40, and 1–44 in three studied families, underlies SCA15 in humans. Public Library of Science 2007-06 2007-06-22 /pmc/articles/PMC1892049/ /pubmed/17590087 http://dx.doi.org/10.1371/journal.pgen.0030108 Text en This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article van de Leemput, Joyce Chandran, Jayanth Knight, Melanie A Holtzclaw, Lynne A Scholz, Sonja Cookson, Mark R Houlden, Henry Gwinn-Hardy, Katrina Fung, Hon-Chung Lin, Xian Hernandez, Dena Simon-Sanchez, Javier Wood, Nick W Giunti, Paola Rafferty, Ian Hardy, John Storey, Elsdon Gardner, R. J. McKinlay Forrest, Susan M Fisher, Elizabeth M. C Russell, James T Cai, Huaibin Singleton, Andrew B Deletion at ITPR1 Underlies Ataxia in Mice and Spinocerebellar Ataxia 15 in Humans |
title | Deletion at ITPR1 Underlies Ataxia in Mice and Spinocerebellar Ataxia 15 in Humans |
title_full | Deletion at ITPR1 Underlies Ataxia in Mice and Spinocerebellar Ataxia 15 in Humans |
title_fullStr | Deletion at ITPR1 Underlies Ataxia in Mice and Spinocerebellar Ataxia 15 in Humans |
title_full_unstemmed | Deletion at ITPR1 Underlies Ataxia in Mice and Spinocerebellar Ataxia 15 in Humans |
title_short | Deletion at ITPR1 Underlies Ataxia in Mice and Spinocerebellar Ataxia 15 in Humans |
title_sort | deletion at itpr1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1892049/ https://www.ncbi.nlm.nih.gov/pubmed/17590087 http://dx.doi.org/10.1371/journal.pgen.0030108 |
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