Disease relevance of ATXN8OS

• An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8) [1].
• Two major ancestrally related haplotypes (A and A') were found among white families with ataxia, normal controls, and patients with major psychosis, indicating a common ancestral origin of both pathogenic and nonpathogenic SCA8 expansions among whites [2].
• We reported elsewhere that an untranslated CTG expansion causes the dominantly inherited neurodegenerative disorder spinocerebellar ataxia type 8 (SCA8) [2].
• False-positive SCA8 gene test in a patient with pathologically proven multiple system atrophy [3].
• A moderate SCA8 expansion (85-97 repeats) was found in two unrelated families with slowly progressive cerebellar ataxia [4].

Psychiatry related information on ATXN8OS

• Five unrelated ataxic patients with the SCA 8 expansion and a sixth identified subsequently had clinical and psychometric assessment; the clinical features were available in a seventh [5].
• RESULTS: SCA8 patients demonstrated deficits primarily in attention and information processing, as well as in concept formation, reasoning, executive functions and verbal production [6].
• In none of the SCA8 studies have the neuropsychological test performances been the primary measures [6].

High impact information on ATXN8OS

• We previously reported that a (CTG)n expansion causes spinocerebellar ataxia type 8 (SCA8), a slowly progressive ataxia with reduced penetrance [7].
• Moreover, the expression of noncoding (CUG)n expansion transcripts (ataxin 8 opposite strand, ATXN8OS) and the discovery of intranuclear polyglutamine inclusions suggests SCA8 pathogenesis involves toxic gain-of-function mechanisms at both the protein and RNA levels [7].
• The neurological phenotype in SCA8 BAC expansion but not BAC control lines demonstrates the pathogenicity of the (CTG-CAG)n expansion [7].
• 1C2-positive intranuclear inclusions in cerebellar Purkinje and brainstem neurons in SCA8 expansion mice and human SCA8 autopsy tissue result from translation of a polyglutamine protein, encoded on a previously unidentified antiparallel transcript (ataxin 8, ATXN8) spanning the repeat in the CAG direction [7].
• Large, expanded repeats in SCA8 are not confined to patients with cerebellar ataxia [8].

Chemical compound and disease context of ATXN8OS

• In a recent article, we described a patient with ataxia carrying reduced serum vitamin E levels and showing CTA/CTG expansions of 320 triplet repeats in the SCA8 gene [9].
• SCA8 was the first example of a dominant spinocerebellar ataxia that is not caused by the expansion of a CAG repeat translated into a polyglutamine tract [10].

Biological context of ATXN8OS

• Human and mouse KLHL1AS are transcribed from homologous promoter regions in the first intron of KLHL1 and extend through the transcription and translation start sites as well as the first splice donor sequence of KLHL1 [11].
• SCA8 shows a complex inheritance pattern with extremes of incomplete penetrance, in which often only one or two affected individuals are found in a given family [2].
• Recently, an untranslated (CTG)n expansion on chromosome 13q was described as being the cause of SCA8 [12].
• In conclusion, our results show (1) no overlapping between control (15-91) and pathogenic (100-152) alleles and (2) a high instability in spermatogenesis (both for expanded and normal alleles), suggesting a high mutational rate at the SCA8 locus [12].
• Spinocerebellar ataxia type 8 (SCA8) is a neurodegenerative disorder caused by the expansion of a CTG trinucleotide repeat that is transcribed as part of an untranslated RNA [13].

Anatomical context of ATXN8OS

• Similarly, human KLHL1AS is expressed in various brain tissues, including the cerebellum, the tissue most affected by SCA8, and was detected at low levels in testis and kidney [11].
• The clinical findings include cerebellar ataxia with upper motor neuron dysfunction, dysphagia, peripheral sensory disturbances, or cognitive and psychiatric impairments, indicating phenotypic variability in SCA8 [14].

Associations of ATXN8OS with chemical compounds

• SCA8 is the first example of a dominant SCA not caused by a CAG expansion translated as a polyglutamine tract [1].
• It has been established by combined absorption and fluorescence measurements that the cationic dye Oxazine 1 (OX) and the polyvalent anionic host calix[8]arenesulfonate (SCA8) form two complexes in simultaneous reactions: OX + SCA8 <--> OX.SCA8 (1), and OX.SCA8 + OX <--> OX(2).SCA8 (2) [15].

Other interactions of ATXN8OS

• The evolutionary conservation of this antisense/sense transcriptional organization strongly indicates that KLHL1AS transcripts play a significant biological role in both human and mouse, presumably as a regulator of KLHL1 expression [11].
• Analysis of SCA8 and SCA12 loci in 134 Italian ataxic patients negative for SCA1-3, 6 and 7 CAG expansions [4].

Analytical, diagnostic and therapeutic context of ATXN8OS

• Polymorphism of trinucleotide repeats in non-translated regions of SCA8 and SCA12 genes: allele distribution in a Polish control group [16].
• Sizing of SCA8 alleles should not be a routine diagnostic test until its etiologic role is clarified and the pathogenic threshold is determined [17].
• Although the rarity of major psychosis patients carrying the SCA8 expansion mutation would require a much larger sample size to reach statistical significance, these results support the previously reported observation of increased occurrence of large repeats at SCA8 in major psychosis [18].

References