Generation and characterization of Sca2 (ataxin-2) knockout mice

Kiehl, Tim Rasmus; Nechiporuk, Alex; Figueroa, Karla P.; Keating, Mark T.; Huynh, Duong P.; Pulst, Stefan M.

doi:10.1016/j.bbrc.2005.10.186

Cited by 123 publications

(131 citation statements)

References 28 publications

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“…Significant distortion either of homozygous or of heterozygous Ataxin-2-deficient mice with regard to wild type might be reminiscent of the current distortion. 36 Short ANs might be variants with partial loss of function and large ANs variants with partial gain of function. The former group may be negatively selected.…”

Section: Discussionmentioning

confidence: 99%

Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles

Laffita-Mesa¹,

Velázquez‐Pérez²,

Falcón³

et al. 2011

Eur J Hum Genet

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The role of short, large or intermediate normal alleles (ANs) of the ataxin-2 gene in generating expanded alleles (EAs) causing spinocerebellar ataxia type 2 (SCA2) is poorly understood. It has been postulated that SCA2 prevalence is related to the frequency of large ANs. SCA2 shows the highest worldwide prevalence in Cuban population, which is therefore a unique source for studying the relationship between the frequency of large and intermediate alleles and the frequency of SCA2 mutation. Through genetic polymorphism analyses in a comprehensive sample (B3000 chromosomes), we show that the frequency of large ANs in the ataxin-2 gene is the highest worldwide, although short ANs are also frequent. This highly polymorphic population displayed also high variability in the CAG sequence, featured by loss of the anchor CAA interruption(s). In addition, large ANs showed germinal and somatic instability. Our study also includes related genotypic, genealogical and haplotypic data and provides substantial evidence with regard to the role of large and intermediate alleles in the generation of pathological EAs.

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Section: Discussionmentioning

confidence: 99%

Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles

Laffita-Mesa¹,

Velázquez‐Pérez²,

Falcón³

et al. 2011

Eur J Hum Genet

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“…These data suggest that poly-Q expansion is neomorphic in DRPLA pathogenesis. Considering that disruption of wild-type genes did not cause neurodegeneration in the cases of SCA2 and SCA3 as well (Kiehl et al, 2006;Schmitt et al, 2007), it is possible that poly-Q expansion also plays a neomorphic role in these diseases independent of any functional interaction with the wild-type endogenous proteins. In contrast, HD may be induced by a somewhat different mechanism because the disruption of Huntingtin is sufficient to induce neurodegeneration (Dragatsis et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

C‐terminal deletion of the atrophin‐1 protein results in growth retardation but not neurodegeneration in mice

Ying

Zhuang

et al. 2009

Developmental Dynamics

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Dentatorubral-pallidoluysian atrophy (DRPLA) is a dominant hereditary neurodegenerative disorder caused by the expansion of a poly-glutamine (poly-Q) repeat in Atrophin-1 protein. Ectopic expression of a poly-Q expanded human Atrophin-1 is sufficient to induce DRPLA phenotypes in mice. However, it is still unclear whether the dominant effect of poly-Q expansion is due to the functional interference with wildtype Atrophin-1 proteins, which exist in both patients and transgenic mice. Here we report the generation and analysis of an Atrophin-1 targeting allele that expresses a truncated protein lacking both the poly-Q repeat and following C-terminal peptides. Homozygous mutants exhibit growth retardation and progressive male infertility, but no obvious signs of neurodegeneration. Moreover, the mutant allele neither blocked nor enhanced the neurodegenerative phenotypes caused by a poly-Q expanded transgene. These results support the model that poly-Q expanded Atrophin-1 proteins cause DRPLA in a manner independent of any functional interaction with wild-type Atrophin-1 proteins.

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“…Ataxin‐2 knock‐out mice are viable and only show increased weight gain on a fat‐enriched diet, overall suggesting that ataxin‐2, although widely expressed, is not essential in development 19. There are several evidences that it plays a role in RNA processing, in regulating the calcium release from the endoplasmic reticulum, in the assembly of stress granules and endocytic trafficking of epidermal growth factor receptor.…”

Section: Protein and Its Functionmentioning

confidence: 99%

The Multiple Faces of Spinocerebellar Ataxia type 2

Antenora

Rinaldi

Roca

et al. 2017

Ann Clin Transl Neurol

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Spinocerebellar ataxia type 2 (SCA2) is among the most common forms of autosomal dominant ataxias, accounting for 15% of the total families. Occurrence is higher in specific populations such as the Cuban and Southern Italian. The disease is caused by a CAG expansion in ATXN2 gene, leading to abnormal accumulation of the mutant protein, ataxin‐2, in intracellular inclusions. The clinical picture is mainly dominated by cerebellar ataxia, although a number of other neurological signs have been described, ranging from parkinsonism to motor neuron involvement, making the diagnosis frequently challenging for neurologists, particularly when information about the family history is not available. Although the functions of ataxin‐2 have not been completely elucidated, the protein is involved in mRNA processing and control of translation. Recently, it has also been shown that the size of the CAG repeat in normal alleles represents a risk factor for ALS, suggesting that ataxin‐2 plays a fundamental role in maintenance of neuronal homeostasis.

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Generation and characterization of Sca2 (ataxin-2) knockout mice

Cited by 123 publications

References 28 publications

Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles

Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles

C‐terminal deletion of the atrophin‐1 protein results in growth retardation but not neurodegeneration in mice

The Multiple Faces of Spinocerebellar Ataxia type 2

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