An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8)

Abstract

Myotonic dystrophy (DM) is the only disease reported to be caused by a CTG expansion. We now report that a non-coding CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). This expansion, located on chromosome 13q21, was isolated directly from the genomic DNA of an ataxia patient by RAPID cloning. SCA8 patients have expansions similar in size (107-127 CTG repeats) to those found among adult-onset DM patients. SCA8 is the first example of a dominant SCA not caused by a CAG expansion translated as a polyglutamine tract.

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Figure 1: RAPID cloning of the SCA8 expanded CTG repeat.
Figure 2: Large SCA8 kindred.
Figure 3: PCR analysis of SCA8 CTG affected and normal alleles.
Figure 4: Intergenerational variation in repeat number for maternal and paternal transmissions.
Figure 5: The SCA8 repeat is transcribed exclusively in the CTG orientation and is present in the 3´ terminal exon of a fully processed transcript.

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Acknowledgements

We thank family members for their participation, C. Peterson, H. Lipe and D. Nochlin for help developing the pedigrees and H. Orr for critically reading the manuscript. This work was supported by grants from the National Ataxia Foundation, the Bob Allison Ataxia Research Center, VA research funds and the National Institutes of Health (P01 NS33718 and RO1 NS36282).

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Correspondence to Michael D. Koob or Laura P.W. Ranum.

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