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NEUROLOGY 2006;67:607-613
© 2006 American Academy of Neurology

The role of ataxin 10 in the pathogenesis of spinocerebellar ataxia type 10

M. Wakamiya, PhD, T. Matsuura, MD, Y. Liu, BA, G. C. Schuster, BA, R. Gao, MD, W. Xu, PhD, P. S. Sarkar, PhD, X. Lin, MD, PhD and T. Ashizawa, MD

From the Department of Neurology (M.W., Y.L., R.G., W.X., P.S., X.L., T.A.), University of Texas Medical Branch, Galveston, and Department of Molecular and Human Genetics (T.M., G.C.S.), Baylor College of Medicine, Houston, TX. Dr. Matsuura is currently with the Division of Neurogenetics and Bioinformatics at the Nagoya University Graduate School of Medicine, Japan.

Address correspondence and reprint requests to Dr. T. Ashizawa, Department of Neurology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0539; e-mail: teashiza{at}utmb.edu

Background: Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder characterized by cerebellar ataxia and seizures. SCA10 is caused by an expansion of an ATTCT pentanucleotide repeat in intron 9 of the ataxin 10 (ATXN10) gene encoding an approximately 55-kd protein of unknown function. However, how this mutation leads to SCA10 is unknown.

Methods: In an effort to understand the pathogenic mechanism of SCA10, the authors conducted a series of experiments to address the effect of repeat expansion on the transcription and RNA processing of the ATXN10 gene. In addition, we generated Sca10 (mouse ataxin 10 homolog)–null mice and addressed the role of Sca10 gene dosage on the cerebellum.

Results: Mutant ATXN10 allele is transcribed at the normal level, and the pre-mRNA containing an expanded repeat is processed normally in patient-derived cells. Sca10-null mice exhibited embryonic lethality. Heterozygous mutants were overtly normal and did not develop SCA10 phenotype

Conclusion: A simple gain of function or loss of function of ATXN10 is unlikely to be the major pathogenic mechanism contributing to the spinocerebellar ataxia type 10 phenotype.

This article was previously published in electronic format as an Expedited E-Pub on June 7, 2006, at www.neurology.org.

Supported by NIH grant R01-NS041547 (T.A.). T.M. is supported by National Ataxia Foundation, National Organization for Rare Disorders, the Ichiro Kanehara Foundation (Tokyo), and Brain Science Foundation (Tokyo).

Disclosure: The authors report no conflicts of interest.

Received November 16, 2005. Accepted in final form March 31, 2006.






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