TY - JOUR
T1 - Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans
AU - van de Leemput, Joyce
AU - Chandran, Jayanth
AU - Knight, Melanie A
AU - Holtzclaw, Lynne A
AU - Scholz, Sonja
AU - Cookson, Mark R
AU - Houlden, Henry
AU - Gwinn-Hardy, Katrina
AU - Fung, H C
AU - Lin, Xian
AU - Hernandez, Dena
AU - Simon-Sanchez, Javier
AU - Wood, Nicholas
AU - Giunti, Paola
AU - Rafferty, Ian
AU - Hardy, John
AU - Storey, Elsdon
AU - Gardner, R
AU - Forrest, Susan M
AU - Fisher, Elizabeth M C
AU - Russell, James T
AU - Cai, Huaibin
AU - Singleton, Andrew B
PY - 2007
Y1 - 2007
N2 - 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.
AB - 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.
UR - http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030108
U2 - 10.1371/journal.pgen.0030108
DO - 10.1371/journal.pgen.0030108
M3 - Article
SN - 1553-7390
VL - 3
SP - 1076
EP - 1082
JO - PLoS Genetics
JF - PLoS Genetics
IS - 6
ER -