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Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans

van de Leemput, J; Chandran, J; Knight, MA; Holtzclaw, LA; Scholz, S; Cookson, MR; Houlden, H; ... Singleton, AB; + view all (2007) Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genetics , 3 (6) , Article e108. 10.1371/journal.pgen.0030108. Green open access

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Abstract

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 (Itpr1D18/D18), 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 59 part of the ITPR1 gene, encompassing exons 1-10, 1-40, and 1-44 in three studied families, underlies SCA15 in humans.

Type: Article
Title: Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.0030108
Publisher version: http://dx.doi.org/10.1371/journal.pgen.0030108
Language: English
Additional information: 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.
Keywords: Inositol 1,4,5-trisphosphate receptor, multiple sulfatase deficiency, gene, mouse, discovery, locus
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/1387386
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