HGNC Approved Gene Symbol: ATXN8
SNOMEDCT: 715753001;
Cytogenetic location: 13q21 Genomic coordinates (GRCh38) : 13:54,700,001-72,800,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q21 | Spinocerebellar ataxia 8 | 608768 | Autosomal dominant | 3 |
Spinocerebellar ataxia-8 (SCA8; 608768) is a neurodegenerative disorder caused by a CTG/CAG trinucleotide repeat expansion on chromosome 13q21 (see 603680.0001 and 613289.0001). Two genes span the CTG/CAG repeat and are expressed in opposite directions: ATXN8, which encodes a nearly pure polyglutamine expansion protein in the CAG direction, and ATXN8OS (603680), which, when transcribed, produces a noncoding CUG expansion RNA (Moseley et al., 2006).
Using transgenic mice expressing human BAC clones with and without the SCA8 CTG expansion, Moseley et al. (2006) found that the BAC was transcribed in both directions, resulting in both CAG-containing ATXN8 transcripts and CUG-containing ATXN8OS transcripts. Only ATXN8 was translated into protein, which was predicted to contain an initiating methionine followed by a polyglutamine repeat broken only by 2 arg residues near its C terminus. Western blot analysis of transfected HEK293 cells detected ATXN8 at an apparent molecular mass of 40 kD, with variations in size dependent upon the length of the polyglutamine repeat. Immunohistochemical analysis showed that ATXN8 accumulated in nuclear inclusions in Purkinje, medullary, and dentate neurons from human SCA8 autopsy tissue, but not in normal control tissue. ATXN8 intranuclear inclusions were also detected in Purkinje cells and other neurons of SCA8 BAC expansion mice. Moseley et al. (2006) noted that the SCA8 repeat region is not conserved in mice.
By genomic sequence analysis, Moseley et al. (2006) mapped the ATXN8 gene to chromosome 13q21, where it overlaps the ATXN8OS gene in the opposite orientation.
Moseley et al. (2006) identified IC2-immunoreactive intranuclear inclusions, detecting polyglutamine expansions, in brain tissue from patients with SCA8, but not in normal controls. The polyglutamine protein was determined to be ATXN8 resulting from an expanded CAG repeat (613289.0001). A complementary expanded CTG repeat in the opposite strand, encoded by the ATXN8OS gene (603680.0001), was identified in patients with SCA8 and shown to result in transcription of a toxic mRNA with an expanded CUG repeat (Koob et al., 1999). Thus, the findings of Moseley et al. (2006) indicated that bidirectional transcription at the SCA8 locus results in expression of both a polyglutamine protein and a CUG expansion transcript, which may represent a toxic gain of function at both the protein and RNA levels.
For further information on the SCA8 transgenic mouse model reported by Moseley et al. (2006), see 603680.
Moseley et al. (2006) identified IC2-immunoreactive intranuclear inclusions, detecting polyglutamine expansions, in brain tissue from patients with spinocerebellar ataxia-8 (SCA8; 608768), but not in normal controls. The polyglutamine protein was determined to be ATXN8 resulting from an expanded CAG repeat. A complementary expanded CTG repeat in the opposite strand, encoded by the ATXN8OS gene (603680.0001), was identified in patients with SCA8 and shown to result in transcription of a toxic mRNA with an expanded CUG repeat (Koob et al., 1999). Thus, the findings of Moseley et al. (2006) indicated that bidirectional transcription at the SCA8 locus results in expression of both a polyglutamine protein and a CUG expansion transcript, which may represent a toxic gain of function at both the protein and RNA levels.
Koob, M. D., Moseley, M. L., Schut, L. J., Benzow, K. A., Bird, T. D., Day, J. W., Ranum, L. P. W. An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8). Nature Genet. 21: 379-384, 1999. [PubMed: 10192387] [Full Text: https://doi.org/10.1038/7710]
Moseley, M. L., Zu, T., Ikeda, Y., Gao, W., Mosemiller, A. K., Daughters, R. S., Chen, G., Weatherspoon, M. R., Clark, H. B., Ebner, T. J., Day, J. W., Ranum. L. P. W. Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nature Genet. 38: 758-769, 2006. [PubMed: 16804541] [Full Text: https://doi.org/10.1038/ng1827]