Large Polyglutamine Repeats Cause Muscle Degeneration in SCA17 Mice

Huang, Shanshan; Su, Yang; Guo, Jifeng; Yan, Shihai; Gaertig, Marta A.; Li, Shihua; Li, Shengbo Eben

doi:10.1016/j.celrep.2015.08.060

Cited by 43 publications

(54 citation statements)

References 45 publications

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“…SMAD3 was essential for regulating muscle growth by interacting with other muscle specific regulatory factors (Liu et al 2001;Ge et al 2011;Sriram et al 2014). It was known that muscle development and growth could partly determine body weight in animals (Huang et al 2015). Thus, the current observations in this study together with previous studies raised the possibility that SMAD3 was a potential mediator of bovine body weight and phenotype.…”

Section: Discussionsupporting

confidence: 52%

Genetic variation, association analysis, and expression pattern of SMAD3 gene in Chinese cattle

Shi¹,

Xu²,

Yang³

et al. 2016

CZECH J ANIM SCI

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SMAD3, a member of SMAD transcription factors, plays a key role in transforming growth factorbeta (TGF-β) signalling pathway and regulation of muscle growth. However, there was no strong evidence of association between SMAD3 polymorphisms and body traits in animals. In this study, single nucleotide polymorphisms (SNPs) in SMAD3 gene were detected in four Chinese cattle breeds (Qinchuan, Jiaxian, Nanyang, and Caoyuan) by using DNA pool sequencing and PCR-RFLP, and their effects on gene expression and growth traits were evaluated in Qinchuan cattle. The results showed that four novel SNPs (NC_007308.5 c.-2017A>G, g.101664C>G, g.105829A>G, and g.114523A>G) in promoter, intron 3, and intron 5 were found in four cattle breeds. NC_007308.5 c.-2017A>G and g.114523A>G were significantly (P < 0.05) associated with SMAD3 gene expression. Furthermore, the four SNPs were strikingly (P < 0.05) associated with rump length, chest girth, and body weight in two-year-old Qinchuan cattle. Our results provided the evidence that SNPs in SMAD3 were associated with cattle traits, which showed the possibility that the four SNPs could be novel molecular markers for beef cattle breeding and genetics.

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Section: Discussionsupporting

confidence: 52%

Genetic variation, association analysis, and expression pattern of SMAD3 gene in Chinese cattle

Shi¹,

Xu²,

Yang³

et al. 2016

CZECH J ANIM SCI

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“…In 2011, a knock‐in mouse model of SCA17 was generated and expected to most closely recapitulate SCA17 genetically (Huang et al, ). This knock‐in SCA17 mouse model uses the Cre‐loxP technique, which allows for tissue‐ and time‐specific expression of mutant TBP (Yang et al, ; Huang et al, ). In the knock‐in mouse model, the mouse TBP exon 2 was replaced with human TBP exon 2 carrying 105 CAGs (Huang et al, ).…”

Section: Generation Of Sca17 Animal Modelsmentioning

confidence: 99%

“…In 2015, Huang et al reported the generation of germline TBP knock‐in mice by crossing the floxed TBP mice with transgenic mice expressing Cre under the control of the EIIa promoter, which drives the expression of Cre in early embryonic cells. Therefore, mutant TBP can be expressed ubiquitously at the endogenous level in the crossed mice (Huang et al, ). In this mouse model, the presence of mutant TBP reduced the level of wild‐type TBP in mouse brains, which was also reported previously in the transgenic mice, indicating that TBP is an important transcriptional regulator and that its protein level is tightly controlled in the body.…”

Section: Generation Of Sca17 Animal Modelsmentioning

confidence: 99%

“…In this mouse model, the presence of mutant TBP reduced the level of wild‐type TBP in mouse brains, which was also reported previously in the transgenic mice, indicating that TBP is an important transcriptional regulator and that its protein level is tightly controlled in the body. Moreover, in the germline TBP knock‐in mice, mutant TBP was found to preferentially accumulate in the nuclei of neuronal and muscle cells and exerted polyQ length‐dependent toxic effects in the brain and muscle tissues (Huang et al, ).…”

Section: Generation Of Sca17 Animal Modelsmentioning

confidence: 99%

“…They crossed the floxed TBP mice with muscle‐specific Cre transgenic mice and found that the muscle‐specific expression of mutant TBP produced the same muscle atrophy phenotype. Also, electron microscopic study and immunohistochemical staining did not uncover any abnormal structures in the neuromuscular junction (Huang et al, ).…”

Section: Generation Of Sca17 Animal Modelsmentioning

confidence: 99%

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Genetically modified rodent models of SCA17

Cui

et al. 2016

J of Neuroscience Research

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Spinocerebellar ataxia type 17 (SCA17) is a family member of Autosomal Dominant Cerebellar Ataxias (ADCA) characterized by variable manifestations, including cerebellar ataxia, dementia and psychiatric symptoms. Since the identification of a CAG repeat expansion in the TBP gene in a patient with ataxia in 1999 and then verification of this expansion in SCA17 patients in 2001, several SCA17 rodent models, including both knock-in and transgenic models in mouse and rat, have been established to explore the phenotypic features and pathogenesis of SCA17. These animal models revealed different pathologic changes and phenotypes that are associated with the expression of mutant TBP protein and the CAG repeat lengths. It is important to understand how mutant TBP can cause differential pathological events in SCA17 animal models. In this review, we summarize and compare these animal models for the nature of transgenes and their expression as well as phenotypical features. We also discuss potential directions to use them for future studies.

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Body Mass Index Is Significantly Associated With Disease Severity in Spinocerebellar Ataxia Type 2 Patients

et al. 2021

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A BS TRACT: Background: Spinocerebellar ataxia type 2 is a progressive neurodegenerative disorder due to an unstable expansion of a CAG repeat in the ATXN2 gene. Although weight loss has been associated with disease progression in several neurodegenerative conditions, it has been barely assessed in patients with spinocerebellar ataxia type 2. Objective: The objective of this study was to test whether body mass index is altered in patients with spinocerebellar ataxia type 2 with varying expansion sizes from early to late disease stages. Methods: A cross-sectional case-control study was performed, which included 222 clinically and molecularly diagnosed patients and 214 sex-and age-matched healthy individuals. ATXN2 genotypes and sex were considered as risk factors. Clinical outcomes included the body mass index, age at onset, disease duration, Scale for the Assessment and Rating of Ataxia score, disease stage, dysphagia, and progression rate. Multiple linear regression models were generated.Results: Body mass index was significantly decreased in male patients, but not in female patients, relative to control subjects. In addition to sex, body mass index was significantly associated with age at onset and progression rate. Conversely, body mass index, along with repeat length in ATXN2 expanded alleles and disease duration, was associated with Scale for the Assessment and Rating of Ataxia score. In addition, body mass index, along with the age at onset and the repeat length in ATXN2 normal and expanded alleles, has a significant influence on progression rate. Conclusions: Body mass index might be a useful biomarker of disease severity, particularly in male patients with spinocerebellar ataxia type 2 in the context of nutritional interventions or clinical trials assessing the efficacy of promising new drugs.

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Large Polyglutamine Repeats Cause Muscle Degeneration in SCA17 Mice

Cited by 43 publications

References 45 publications

Genetic variation, association analysis, and expression pattern of SMAD3 gene in Chinese cattle

Genetic variation, association analysis, and expression pattern of SMAD3 gene in Chinese cattle

Genetically modified rodent models of SCA17

Body Mass Index Is Significantly Associated With Disease Severity in Spinocerebellar Ataxia Type 2 Patients

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