• Register
X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

X

Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.

No
Yes

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 we show here that this disorder is caused by a homozygous in-frame 18-bp deletion in Itpr1 (Itpr1(Delta18/Delta18)), 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.

Pubmed ID: 17590087

Authors

  • van de Leemput J
  • Chandran J
  • Knight MA
  • Holtzclaw LA
  • Scholz S
  • Cookson MR
  • Houlden H
  • Gwinn-Hardy K
  • Fung HC
  • Lin X
  • Hernandez D
  • Simon-Sanchez J
  • Wood NW
  • Giunti P
  • Rafferty I
  • Hardy J
  • Storey E
  • Gardner RJ
  • Forrest SM
  • Fisher EM
  • Russell JT
  • Cai H
  • Singleton AB

Journal

PLoS genetics

Publication Data

June 9, 2007

Associated Grants

  • Agency: Medical Research Council, Id: G0500288
  • Agency: Medical Research Council, Id: G0701075
  • Agency: Medical Research Council, Id: G108/638

Mesh Terms

  • Animals
  • Base Sequence
  • Cell Line, Transformed
  • Female
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Sequence Deletion
  • Spinocerebellar Ataxias