title: Spinocerebellar ataxia type 15 (sca15) maps to 3p24.2-3pter: exclusion of the ITPR1 gene, the human orthologue of an ataxic mouse mutant.
abstract: We have studied a large Australian kindred with a dominantly inherited pure cerebellar ataxia, SCA15. The disease is characterised by a very slow rate of progression in some family members, and atrophy predominantly of the superior vermis, and to a lesser extent the cerebellar hemispheres. Repeat expansion detection failed to identify either a CAG/CTG or ATTCT/AGAAT repeat expansions segregating with the disease in this family. A genome-wide scan revealed significant evidence for linkage to the short arm of chromosome 3. The highest two-point LOD score was obtained with D3S3706 (Z = 3.4, theta = 0.0). Haplotype analysis identified recombinants that placed the SCA15 locus within an 11.6-cM region flanked by the markers D3S3630 and D3S1304. The mouse syntenic region contains two ataxic mutants, itpr1-/- and opt, affecting the inositol 1,4,5-triphosphate type 1 receptor, ITPR1 gene. ITPR1 is predominantly expressed in the cerebellar Purkinje cells. Mutation analysis from two representative affected family members excluded the coding region of the ITPR1 gene from being involved in the pathogenesis of SCA15. Thus, the itpr1-/- and opt ITPR1 mouse mutants, which each result in ataxia, are not allelic to the human SCA15 locus.
authors.affiliation: Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Melbourne, Australia.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Knight
authors.forename: Marina L
authors.initials: ML
authors.lastname: Kennerson
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Anney
authors.forename: Tohru
authors.initials: T
authors.lastname: Matsuura
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
authors.forename: Peyman
authors.initials: P
authors.lastname: Salimi-Tari
authors.forename: R J McKinlay
authors.initials: RJ
authors.lastname: Gardner
authors.forename: Elsdon
authors.initials: E
authors.lastname: Storey
authors.forename: Susan M
authors.initials: SM
authors.lastname: Forrest
mesh_terms: D000818:Animals; D001315:Australia; D001483:Base Sequence; D015139:Blotting, Southern; D015220:Calcium Channels / Q000235:genetics*; D002524:Cerebellar Ataxia / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3; D008040:Genetic Linkage; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008126:Lod Score; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion
chemical_list: D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear