van de Leemput, J.C.H.; (2009) Molecular genetic characterization of ataxic movement disorders in mouse and human. Doctoral thesis , UCL (University College London).

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Abstract

Deletion at ITPR1 underlies a young onset autosomal recessive ataxia in mice and a late onset autosomal dominant ataxia (SCA15) in humans. Data presented show the utility of investigating spontaneous mouse mutations in understanding human disease. Through linkage and sequence analysis a novel mutation in the gene encoding inositol 1,4,5-triphosphate receptor type 1 was identified to underlie a severe movement disorder in mice. The 18bp in frame deletion in Itpr1 exon 36 was shown to be allelic to that of another model, opisthotonos (Lane 1972). The Itpr1Δ18 mutation leads to a decreased to almost total lack in the normally high level of ITPR1 expression in cerebellar Purkinje cells. In addition, high density genome wide SNP genotype data in humans showed a SUMF1-ITPR1 deletion to segregate with spinocerebellar ataxia 15 (SCA15), a late-onset autosomal dominant disorder, which was previously mapped to the genomic region containing ITPR1; however, no causal mutations had been identified (Knight et al. 2003). With this deletion not observed in a control population, decreased ITPR1 protein levels in individuals carrying the deletion, and subsequent identification of similar deletions in additional spinocerebellar ataxia families, the data provide compelling evidence that heterozygous deletion in ITPR1 underlies SCA15. As demonstrated, high density genome wide SNP analysis can facilitate rapid detection of structural genomic mutations that may underlie disease when standard sequencing approaches are insufficient. The data suggest genetic alterations at ITPR1 underlie approximately over 1% of autosomal dominant SCA type III (ADCA III) cases for which currently no genetic cause has been identified. Data described herein add weight to a role for aberrant intracellular Ca2+ signaling in Purkinje cells in the pathogenesis of spinocerebellar ataxia.

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