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, Hon Chung Fung, Xian Lin, Dena Hernandez, Javier Simon-Sanchez, Nick W. Wood, Paola Giunti, Ian Rafferty, John Hardy, Elsdon Storey, R. J.Mc Kinlay Gardner, Susan M. Forrest, Elizabeth M.C. FisherJames T. Russell, Huaibin Cai, Andrew B. Singleton

Research output: Contribution to journalArticlepeer-review

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 (Itpr1Δ18/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.

Original languageEnglish (US)
Pages (from-to)1076-1082
Number of pages7
JournalPLoS genetics
Volume3
Issue number6
DOIs
StatePublished - Jun 2007
Externally publishedYes

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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