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Clinical and Genetic Characterization of Autosomal Recessive Spinocerebellar Ataxia Type 16 (SCAR16) in Taiwan

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Abstract

Mutations in STUB1 have been identified to cause autosomal recessive spinocerebellar ataxia type 16 (SCAR16), also named as Gordon Holmes syndrome, which is characterized by cerebellar ataxia, cognitive decline, and hypogonadism. Additionally, several heterozygous mutations in STUB1 have recently been described as a cause of autosomal dominant spinocerebellar ataxia type 48. STUB1 encodes C-terminus of HSC70-interacting protein (CHIP), which functions as an E3 ubiquitin ligase and co-chaperone and has been implicated in several neurodegenerative diseases. In this study, we identified two SCAR16 pedigrees from 512 Taiwanese families with cerebellar ataxia. Two compound heterozygous mutations in STUB1, c.[433A>C];[721C>T] (p.[K145Q];[R241W]) and c.[433A>C];[694T>G] (p.[K145Q];[C232G]), were found in each SCAR16 family by Sanger sequencing, respectively. Among them, STUB1 p.R241W and p.C232G were novel mutations. SCAR16 seems to be an uncommon ataxic syndrome, accounting for 0.4% (2/512) of our cohort with cerebellar ataxia. Clinically, the three patients from the two SCAR16 families presented with cerebellar ataxia alone or in combination with cognitive impairment. The brain MRIs showed a marked cerebellar atrophy of the patients. In conclusion, SCAR16 is an important but often neglected diagnosis of cerebellar ataxia of unknown cause, and the isolated cerebellar ataxia without involvement of other systems cannot be a basis to exclude the possibility of STUB1-related disease.

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Funding

This work was supported by research grants from the Ministry of Science and Technology (MOST), Taiwan, to B.W.S. (103-2314-B-010-049-MY3, 104-2745-B-010-004, 106-2321-B-010-010, 107-2314-B-010-017). This work was also financially supported by the Brain Research Center, National Yang-Ming University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan.

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Authors and Affiliations

  1. Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan

    Hsu-Huai Chiu, Yi-Chu Liao, Yi-Chung Lee & Bing-Wen Soong

  2. Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan

    Hsu-Huai Chiu, Cheng-Tsung Hsaio, Yi-Chu Liao, Yi-Chung Lee & Bing-Wen Soong

  3. Division of Neurology, Department of Internal Medicine, Taipei Veterans General Hospital Taoyuan Branch, Taoyuan, Taiwan

    Cheng-Tsung Hsaio

  4. Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan

    Cheng-Tsung Hsaio

  5. Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan

    Yu-Shuen Tsai

  6. Center for Systems and Synthetic Biology, National Yang-Ming University, Taipei, Taiwan

    Yu-Shuen Tsai

  7. Brain Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan

    Yi-Chu Liao, Yi-Chung Lee & Bing-Wen Soong

  8. Taipei Neuroscience Institute, Taipei Medical University, Taipei, Taiwan

    Bing-Wen Soong

  9. Department of Neurology, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan

    Bing-Wen Soong

Authors
  1. Hsu-Huai Chiu
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  2. Cheng-Tsung Hsaio
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  3. Yu-Shuen Tsai
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  4. Yi-Chu Liao
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  5. Yi-Chung Lee
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  6. Bing-Wen Soong
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Contributions

Y.C. Lee and B.W.S. conceived and designed the study. H.H.C., C.T.H., and B.W.S. collected patient information and executed clinical analyses. Y.S.T. performed the mutational and bioinformatics analysis. H.H.C. and Y.C. Lee drafted the manuscript. C.T.H, Y.C. Liao, Y.C. Lee, and B.W.S. revised the manuscript. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Yi-Chung Lee or Bing-Wen Soong.

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Chiu, HH., Hsaio, CT., Tsai, YS. et al. Clinical and Genetic Characterization of Autosomal Recessive Spinocerebellar Ataxia Type 16 (SCAR16) in Taiwan. Cerebellum 19, 544–549 (2020). https://doi.org/10.1007/s12311-020-01136-4

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  • DOI: https://doi.org/10.1007/s12311-020-01136-4

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