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

Joyce van de Leemput, Jayanth Chandran, Melanie A Knight, Lynne A Holtzclaw, Sonja Scholz, Mark R Cookson, Henry Houlden, Katrina Gwinn-Hardy, H C Fung, Xian Lin, Dena Hernandez, Javier Simon-Sanchez, Nicholas Wood, Paola Giunti, Ian Rafferty, John Hardy, Elsdon Storey, R Gardner, Susan M Forrest, Elizabeth M C FisherJames T Russell, Huaibin Cai, Andrew B Singleton

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213 Citations (Scopus)


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?18/?18), 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.
Original languageEnglish
Pages (from-to)1076 - 1082
Number of pages7
JournalPLoS Genetics
Issue number6
Publication statusPublished - 2007

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