Phenotypic and molecular diversities of spinocerebellar ataxia type 2 in Japan

Inada, Rino; Hirano, Minoru; Oka, Nobuyuki; Samukawa, Makoto; Saigoh, Kazumasa; Suzuki, Hidekazu; Udaka, Fukashi; Hashiguchi, Akihiro; Takashima, Hiroshi; Hamada, Yukihiro; Nakamura, Yusaku; Kusunoki, Susumu

doi:10.1007/s00415-021-10467-z

Cited by 7 publications

(5 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, a previous study did not find any evidence suggesting loss of DNA repair function of RFC1 in fibroblasts 1 . Our electron microscopic findings suggested cytoplasmic inclusions in Schwann cells, a situation similar to that of SCA2-related neuropathy, a gain of function disease 8 . Further accumulation of evidence is needed to clarify the pathomechanism using neuronal or glial cell models or animal models.…”

Section: Discussionsupporting

confidence: 67%

See 1 more Smart Citation

CANVAS-related RFC1 mutations in patients with immune-mediated neuropathy

Hirano,

Kuwahara,

Yamagishi

et al. 2023

Sci Rep

Self Cite

View full text Add to dashboard Cite

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy.

show abstract

Section: Discussionsupporting

confidence: 67%

“…Our previous study showed that CAG repeat expansions in ATXN2 , which causes spinocerebellar ataxia type 2 (SCA2), were found in patients with CIDP or immune-mediated neuropathy 8 . A recent review also suggested the association between repeat expansions and various diseases, including immune-mediated diseases 9 .…”

Section: Introductionmentioning

confidence: 99%

CANVAS-related RFC1 mutations in patients with immune-mediated neuropathy

Hirano,

Kuwahara,

Yamagishi

et al. 2023

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…1,2 To date, at least 50 genetic loci have been reported to be associated with SCA subtypes. 1,[3][4][5][6][7][8] The CAG repeat expansions encode for a polyglutamine (polyQ) stretch underlying the polyQ diseases, 9,10 the polyQ SCAs of which account for the most frequent SCA subtypes. However, over the last two decades, no additional neurodegenerative ataxia has been qualified as polyQ disease.…”

mentioning

confidence: 99%

“…Spinocerebellar ataxias (SCAs) are a group of autosomal dominant neurodegenerative disorders that typically present with cerebellar ataxia and variable nonataxic symptoms 1,2 . To date, at least 50 genetic loci have been reported to be associated with SCA subtypes 1,3‐8 . The CAG repeat expansions encode for a polyglutamine (polyQ) stretch underlying the polyQ diseases, 9,10 the polyQ SCAs of which account for the most frequent SCA subtypes.…”

mentioning

confidence: 99%

CAG Repeat Expansion in THAP11 Is Associated with a Novel Spinocerebellar Ataxia

et al. 2023

View full text Add to dashboard Cite

Background More than 50 loci are associated with spinocerebellar ataxia (SCA), and the most frequent subtypes share nucleotide repeats expansion, especially CAG expansion. Objective The objective of this study was to confirm a novel SCA subtype caused by CAG expansion. Methods We performed long‐read whole‐genome sequencing combined with linkage analysis in a five‐generation Chinese family, and the finding was validated in another pedigree. The three‐dimensional structure and function of THAP11 mutant protein were predicted. Polyglutamine (polyQ) toxicity of THAP11 gene with CAG expansion was assessed in skin fibroblasts of patients, human embryonic kidney 293 and Neuro‐2a cells. Results We identified THAP11 as the novel causative SCA gene with CAG repeats ranging from 45 to 100 in patients with ataxia and from 20 to 38 in healthy control subjects. Among the patients, the number of CAA interruptions within CAG repeats was decreased to 3 (up to 5–6 in controls), whereas the number of 3′ pure CAG repeats was up to 32 to 87 (4–16 in controls), suggesting that the toxicity of polyQ protein was length dependent on the pure CAG repeats. Intracellular aggregates were observed in cultured skin fibroblasts from patients. THAP11 polyQ protein was more intensely distributed in the cytoplasm of cultured skin fibroblasts from patients, which was replicated with in vitro cultured neuro‐2a transfected with 54 or 100 CAG repeats. Conclusions This study identified a novel SCA subtype caused by intragenic CAG repeat expansion in THAP11 with intracellular aggregation of THAP11 polyQ protein. Our findings extended the spectrum of polyQ diseases and offered a new perspective in understanding polyQ‐mediated toxic aggregation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

show abstract

“…As indicated, the new ATXN2 immunoassay is with an assay range of around 1 ng to 10 μg more sensitive as other known techniques to determine protein expression including western blot analyses. But as most techniques, also this kind of immunoassay show some limitations including ran-translation [ 80 ], post-translational protein modifications [ 81 ], but also ATXN2 alternative splicing variants [ 82 ] or genomic mutations [ 48 , 57 , 83 ], which may interfere with the antibody binding sites. ATXN2 is shown to modulate different neurodegenerative diseases like ALS or SCA3 by intermediate repeat length [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

TR-FRET-Based Immunoassay to Measure Ataxin-2 as a Target Engagement Marker in Spinocerebellar Ataxia Type 2

et al. 2023

View full text Add to dashboard Cite

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disease, which belongs to the trinucleotide repeat disease group with a CAG repeat expansion in exon 1 of the ATXN2 gene resulting in an ataxin-2 protein with an expanded polyglutamine (polyQ)-stretch. The disease is late manifesting leading to early death. Today, therapeutic interventions to cure the disease or even to decelerate disease progression are not available yet. Furthermore, primary readout parameter for disease progression and therapeutic intervention studies are limited. Thus, there is an urgent need for quantifiable molecular biomarkers such as ataxin-2 becoming even more important due to numerous potential protein-lowering therapeutic intervention strategies. The aim of this study was to establish a sensitive technique to measure the amount of soluble polyQ-expanded ataxin-2 in human biofluids to evaluate ataxin-2 protein levels as prognostic and/or therapeutic biomarker in SCA2. Time-resolved fluorescence energy transfer (TR-FRET) was used to establish a polyQ-expanded ataxin-2-specific immunoassay. Two different ataxin-2 antibodies and two different polyQ-binding antibodies were validated in three different concentrations and tested in cellular and animal tissue as well as in human cell lines, comparing different buffer conditions to evaluate the best assay conditions. We established a TR-FRET-based immunoassay for soluble polyQ-expanded ataxin-2 and validated measurements in human cell lines including iPSC-derived cortical neurons. Additionally, our immunoassay was sensitive enough to monitor small ataxin-2 expression changes by siRNA or starvation treatment. We successfully established the first sensitive ataxin-2 immunoassay to measure specifically soluble polyQ-expanded ataxin-2 in human biomaterials.

show abstract

Phenotypic and molecular diversities of spinocerebellar ataxia type 2 in Japan

Cited by 7 publications

References 30 publications

CANVAS-related RFC1 mutations in patients with immune-mediated neuropathy

CANVAS-related RFC1 mutations in patients with immune-mediated neuropathy

CAG Repeat Expansion in THAP11 Is Associated with a Novel Spinocerebellar Ataxia

TR-FRET-Based Immunoassay to Measure Ataxin-2 as a Target Engagement Marker in Spinocerebellar Ataxia Type 2

Contact Info

Product

Resources

About