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.
Highlights
The use of forward genetics to define novel loci of interest in human disease has become increasingly viable with the implementation of large-scale mutagenesis programs
We have identified a spontaneous in-frame deletion mutation in the gene Itpr1 that causes a recessive movement disorder in mice
In an attempt to define whether any similar disease occurs in humans we performed a literature search for diseases linked to the human chromosomal region containing ITPR1
Summary
The use of forward genetics to define novel loci of interest in human disease has become increasingly viable with the implementation of large-scale mutagenesis programs. Prior to these initiatives this work was carried out in part by the investigation of spontaneous mutations that cause disorders in mouse breeding colonies. During the generation of a knockout line of mice we noted an early movement disorder that was inherited independently of targeting vector transmission. During the generation of a line of mice with knockout of the gene Park we noted an early movement disorder that was inherited independently of targeting vector transmission.
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