ClinVar Genomic variation as it relates to human health

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. (less)

In patients with spinocerebellar ataxia-8 (SCA8; 608768), Koob et al. (1999) identified a CAG repeat expansion in the 5-prime to 3-prime orientation of the ATXN8 template strand (ATXN8; 613289.0001) that did not appear to be translated into a polyglutamine-containing protein. However, the corresponding 5-prime-to-3-prime CTG repeat expansion in the ATXN8OS gene on the opposite strand was found to be transcribed into an mRNA with an expanded CUG repeat in its 3-prime UTR. The mRNA with the expanded CUG repeat was not translated. Moseley et al. (2006) found that the CAG repeat in the ATXN8 gene was transcribed into a protein with an expanded polyglutamine tract in patients with SCA8. In 37 families with SCA8 ataxia from the United States, Canada, Japan, and Mexico, Ikeda et al. (2004) identified 3 different ancestral haplotypes containing the ATXN8OS gene that segregated with the families according to population: Caucasian, Japanese, and Mexican. Martins et al. (2005) performed haplotype and sequencing analysis in a large region encompassing the ATXN8OS gene (CTA)n (CTG)n repeat and 6 SNP markers in 4 SCA8 families of Portuguese descent. Two different haplotypes, AG-Expanded-GTTG and AG-Expanded-CTTG, were identified. The same haplotypes were also the most frequently identified (AG-Normal-GTTG and AG-Normal-CTTG) in the normal population of 20 control Portuguese families, suggesting that the mutated state arose from common backgrounds. Daughters et al. (2009) presented evidence that the expanded CTG repeat in the ATXN8OS gene is transcribed into an mRNA with an expanded CUG repeat, conferring a toxic gain of function that plays a role in the SCA8 phenotype. In brain tissue from humans and mice with SCA8, ATXN8OS mRNA containing the expanded repeat was found to accumulate as ribonuclear inclusions, or RNA foci, that colocalized with the RNA-binding protein MBNL1 (606516) in selected cerebellar cortical neurons in the brain. Sequestration of MBNL1 in RNA foci resulted in dysregulation of downstream splicing patterns normally regulated by the CUGBP1 (601074)/MBNL1 pathway, including that of mouse GABA transporter-4 (GAT4, or SLC6A11; 607952). These changes in Gat4 were associated with loss of GABAergic inhibition in the granular cell layer. These data indicated that expanded CUG ATXN8OS mRNA transcripts can have a toxic gain of function. Susceptibility to Late-Onset Parkinson Disease Wu et al. (2004) identified repeat expansions at the SCA8 locus in 4 (1.5%) of 264 patients with typical late-onset levodopa-responsive Parkinson disease (168600). The expansions ranged in size from 75 to 92. (less)