Deletion at ITPR1 Underlies Ataxia in Mice and Spinocerebellar Ataxia 15 in Humans

Molecular Genetics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS Genetics (Impact Factor: 7.53). 07/2007; 3(6):e108. DOI: 10.1371/journal.pgen.0030108
Source: PubMed


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.

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Available from: Dena G Hernandez
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    • "The edges 3708 <-9456 that involves the gene Itpr1 and the gene HOMER1 were very interesting. The relationships are involved in the spinocerebellar ataxia in human as described by [46]. Also other links that include the PIRSF adenylate cyclase, GTP-binding regulatory protein and the PLC-beta could be useful to interpret the role of mutation in the progranulin gene group. "
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    ABSTRACT: Background It is currently accepted that the perturbation of complex intracellular networks, rather than the dysregulation of a single gene, is the basis for phenotypical diversity. High-throughput gene expression data allow to investigate changes in gene expression profiles among different conditions. Recently, many efforts have been made to individuate which biological pathways are perturbed, given a list of differentially expressed genes (DEGs). In order to understand these mechanisms, it is necessary to unveil the variation of genes in relation to each other, considering the different phenotypes. In this paper, we illustrate a pipeline, based on Structural Equation Modeling (SEM) that allowed to investigate pathway modules, considering not only deregulated genes but also the connections between the perturbed ones. Results The procedure was tested on microarray experiments relative to two neurological diseases: frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) and multiple sclerosis (MS). Starting from DEGs and dysregulated biological pathways, a model for each pathway was generated using databases information biological databases, in order to design how DEGs were connected in a causal structure. Successively, SEM analysis proved if pathways differ globally, between groups, and for specific path relationships. The results confirmed the importance of certain genes in the analyzed diseases, and unveiled which connections are modified among them. Conclusions We propose a framework to perform differential gene expression analysis on microarray data based on SEM, which is able to: 1) find relevant genes and perturbed biological pathways, investigating putative sub-pathway models based on the concept of disease module; 2) test and improve the generated models; 3) detect a differential expression level of one gene, and differential connection between two genes. This could shed light, not only on the mechanisms affecting variations in gene expression, but also on the causes of gene-gene relationship modifications in diseased phenotypes.
    Full-text · Article · May 2014 · BMC Bioinformatics
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    • "Linkage to 3pter has been demonstrated in one large Australian family (SCA29), which overlaps with the locus for SCA15 [2]. SCA15 is a dominantly inherited slowly progressive cerebellar ataxia with mid-life onset; heterozygous ITPR1 deletions spanning the entire or part of the gene are disease-causing [12-15]. "
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    ABSTRACT: Background Congenital nonprogressive spinocerebellar ataxia is characterized by early gross motor delay, hypotonia, gait ataxia, mild dysarthria and dysmetria. The clinical presentation remains fairly stable and may be associated with cerebellar atrophy. To date, only a few families with autosomal dominant congenital nonprogressive spinocerebellar ataxia have been reported. Linkage to 3pter was demonstrated in one large Australian family and this locus was designated spinocerebellar ataxia type 29. The objective of this study is to describe an unreported Canadian family with autosomal dominant congenital nonprogressive spinocerebellar ataxia and to identify the underlying genetic causes in this family and the original Australian family. Methods and Results Exome sequencing was performed for the Australian family, resulting in the identification of a heterozygous mutation in the ITPR1 gene. For the Canadian family, genotyping with microsatellite markers and Sanger sequencing of ITPR1 gene were performed; a heterozygous missense mutation in ITPR1 was identified. Conclusions ITPR1 encodes inositol 1,4,5-trisphosphate receptor, type 1, a ligand-gated ion channel that mediates calcium release from the endoplasmic reticulum. Deletions of ITPR1 are known to cause spinocerebellar ataxia type 15, a distinct and very slowly progressive form of cerebellar ataxia with onset in adulthood. Our study demonstrates for the first time that, in addition to spinocerebellar ataxia type 15, alteration of ITPR1 function can cause a distinct congenital nonprogressive ataxia; highlighting important clinical heterogeneity associated with the ITPR1 gene and a significant role of the ITPR1-related pathway in the development and maintenance of the normal functions of the cerebellum.
    Full-text · Article · Sep 2012 · Orphanet Journal of Rare Diseases
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    • "It has been reported in more than 20 families from Europe, Japan, and Australia [Klebe et al., 2005]. SCA15/16 is caused by heterozygous deletions of the 5 part of the ITPR1 gene [van de Leemput et al., 2007] although a missense mutation (c.1480G>A p.V494I) has been reported. The ITPR1 protein is highly expressed in cerebellar Purkinje cells and is an important modulator of intracellular calcium signaling. "
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    ABSTRACT: The inherited cerebellar ataxias are a diverse group of clinically and genetically heterogeneous neurodegenerative disorders. Inheritance patterns of these disorders can be complex with autosomal dominant, autosomal recessive, X-linked, and mitochondrial inheritance demonstrated by one or more ataxic syndromes. The broad range of mutation types found in inherited ataxia contributes to the complex genetic etiology of these disorders. The majority of inherited ataxias are caused by repeat expansions; however, conventional mutations are important causes of the rarer dominant and recessive ataxias. Advances in sequencing technology have allowed for much broader testing of these rare ataxia genes. This is relevant to the aims of the Human Variome Project, which aims to collate and store gene variation data through mutation databases. Variant data is currently located in a range of public and commercial resources. Few locus-specific databases have been created to catalogue variation in the dominant ataxia genes although there are several databases for some recessive genes. Developing these resources will facilitate a better understanding of the complex genotype-phenotype relationships in these disorders and assist interpretation of gene variants as testing for rarer ataxia genes becomes commonplace.
    Preview · Article · Sep 2012 · Human Mutation
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