Alternative titles; symbols
HGNC Approved Gene Symbol: ATXN8OS
SNOMEDCT: 715753001;
Cytogenetic location: 13q21.33 Genomic coordinates (GRCh38): 13:70,107,421-70,171,738 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q21.33 | {Parkinson disease, susceptibility to} | 168600 | Autosomal dominant; Multifactorial | 3 |
| 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 (613289), which encodes a nearly pure polyglutamine expansion protein in the CAG direction, and ATXN8OS, which, when transcribed, produces a noncoding CUG expansion RNA (Moseley et al., 2006).
While searching for CAG repeat disorders in patients with undefined dominantly inherited ataxias, Koob et al. (1999) identified 80 uninterrupted CAG repeats followed by 11 TAG repeats in genomic DNA from a mother and daughter with adult-onset spinocerebellar ataxia (SCA8; 608768). The expansion was isolated directly from genomic DNA by RAPID (repeat analysis, pooled isolation, and detection) cloning. By strand-specific analysis, Koob et al. (1999) determined that the SCA8 repeat was transcribed in the CTG orientation (reading 5-prime to 3-prime) on the complementary antisense strand from that of the CAG repeat. Koob et al. (1999) found that the CTG repeat is present in the 3-prime terminal exon of the ATXN8OS gene, which they called SCA8, and is located in the 3-prime UTR of the ATXN8OS transcript, which has no ORFs. RT-PCR on cerebellum RNA from 2 unaffected individuals heterozygous for the SCA8 CTG marker detected both alleles in each RNA sample. Alternatively spliced ATXN8OS transcripts lacking an exon were also detected. The ATXN8OS transcript was detected at low levels in whole brain and lung by RT-PCR. Further analysis identified an mRNA transcribed in the opposite orientation to that of the ATXN8OS transcript, KLHL1 (605332), suggesting that ATXN8OS is an endogenous antisense RNA. The SCA8 CTG repeat is present in the antisense transcript, but not the KLHL1 sense transcript. Although the studies of Koob et al. (1999) indicated that there is no translation of the SCA8 repeat in the CAG orientation into a polyglutamine tract, later studies by Moseley et al. (2006) showed that the CAG repeat on the sense strand is in the ATXN8 gene (613289) and is transcribed and translated.
Koob et al. (1999) determined that the ATXN8OS gene contains 4 exons, at least 1 of which is alternatively spliced.
Nemes et al. (2000) assembled a 166-kb segment of genomic sequence containing the SCA8 repeat. ATXN8OS RNA transcripts containing the SCA8 CUG repeat tract are alternatively spliced, contain up to 5 exons, and span a genomic region of over 32 kb. The SCA8 CUG repeat is in the 3-prime terminal exon of these ATXN8OS transcripts, although Nemes et al. (2000) also identified transcripts with an alternative 3-prime terminal exon that lack the SCA8 repeat. They found that the most 5-prime exon of ATXN8OS is transcribed through the first exon of another gene, KLHL1 (605332), that is transcribed in the opposite orientation. This gene arrangement suggested that the ATXN8OS transcript may be an endogenous antisense RNA that overlaps the transcription and translation start sites as well as the first splice donor sequence of the sense gene, KLHL1. Since both of these genes are expressed in the cerebellum, Nemes et al. (2000) suggested that the pathogenic effect of the expansion may be mediated either directly or indirectly through one or both of these transcripts.
Moseley et al. (2006) determined that the ATXN8OS gene contains at least 6 exons that are subject to extensive alternative splicing.
By PCR analysis of a chromosome hybrid panel and the CEPH library, Koob et al. (1999) mapped the SCA8 CTG expansion, which is located within the 3-prime end of the ATXN8OS gene, to chromosome 13q21. Nemes et al. (2000) determined that the 5-prime end of the ATXN8OS gene overlaps the 5-prime end of the KLHL1 gene (605332) in the opposite orientation. Moseley et al. (2006) determined that the 3-prime end of the ATXN8OS gene, including the CTG expansion region, overlaps the 3-prime end of the ATXN8 gene (613289) in the opposite orientation.
Spinocerebellar Ataxia 8
In 8 pedigrees with autosomal dominant spinocerebellar ataxia-8 (SCA8; 608768), Koob et al. (1999) identified CTG repeat expansions in the ATXN8OS gene (603680.0001), on the opposite stand of the ATXN8 gene (613298). This 5-prime to 3-prime CTG repeat in ATXN8OS resulted in the production of an mRNA with an expanded CUG repeat in the 3-prime UTR. In the largest pedigree, which included affected members spanning at least 4 generations, repeat length ranged from 107 to 127 CTG repeats. However, 20 unaffected individuals also carried expanded repeats. A study of 1,200 alleles from the general population found that normal repeat length was 16 to 37 repeats in 99% of alleles; repeat lengths of up to 91 were seen in a small proportion of controls. Like the CTG expansion in DM, repeat length contracted with paternal transmission (-86 to +7) and expanded with maternal transmission (-11 to +600). Koob et al. (1999) noted that maternal bias towards expansion had not been seen in the CAG repeat disorders causing other SCAs.
Stevanin et al. (2000) and Worth et al. (2000) presented data challenging the significance of the expanded SCA8 repeat in SCA. Among 376 French control chromosomes, Stevanin et al. (2000) found that 373 (99%) carried 3 to 28 repeats, whereas 3 alleles carried expanded repeats of 107, 111, and 123 repeats. Among 250 European index patients with different forms of ataxia, 487 chromosomes contained 2 to 25 repeats and 13 chromosomes (11 patients, including 2 homozygotes) contained 68 to 123 repeats. They found expansions of more than 91 repeats in 8 of 148 autosomal dominant cerebellar ataxia (ADCA) families, in an apparently sporadic ataxia patient, in a patient with neuropathologically confirmed Lafora disease, and in a patient with familial essential tremor. Stevanin et al. (2000) suggested that the expanded repeat is a rare polymorphism. Among 1,306 control chromosomes, Worth et al. (2000) found that 97% contained 15 to 31 repeats, whereas 5 had large, expanded alleles of 174, 133, 103, 101, and 100 repeats. Among 98 unrelated cases of ADCA, 1 patient had alleles with 23 and 152 CTA/CTG repeats. However, the 92-year-old asymptomatic mother of another affected patient carried 127 repeats, and the authors concluded that the expanded alleles may be polymorphisms in linkage disequilibrium with mutations in a different gene on 13q21. Moseley et al. (2000) referred to 5 lines of evidence they thought supported the hypothesis that the SCA8 CTG expansion causes ataxia.
Silveira et al. (2000) found that normal SCA8 chromosomes showed an apparently trimodal distribution, with classes of small (15 to 21 CTGs), intermediate (22 to 37 CTGs), and large (40 to 91 CTGs) alleles; large alleles accounted for only 0.7% of all normal-size alleles. No expanded alleles (more than 100 CTGs) were found in controls. Expansion of the CTG tract was found in 5 families with ataxia; expanded alleles, all paternally transmitted, were characterized mostly by repeat-size contraction. There was a high germinal instability of both expanded and normal alleles: in 1 patient, an expanded allele of 152 CTGs had mostly contraction in size, often into the normal range; in the sperm of 2 normal controls, contractions were also more frequent, but occasional expansions into the upper limit of the normal size range were also seen. In conclusion, their results showed no overlapping between control (15-91) and pathogenic (100-152) alleles, and a high instability in spermatogenesis for both expanded and normal alleles, suggesting a high mutation rate at the SCA8 locus.
In contrast to other triplet repeat diseases, expanded alleles found in affected SCA8 individuals can have either a pure uninterrupted CTG repeat tract or an allele with 1 or more CCG, CTA, CTC, CCA, or CTT interruptions. By analyzing sequence configurations and instability patterns of the CTG repeat in affected and unaffected family members from the large 7-generation SCA8 family reported by Koob et al. (1999), Moseley et al. (2000) found 6 different sequence configurations of the CTG repeat. In 2 instances, duplication of CCG interruptions occurred over a single generation, and in other instances duplications that had occurred in different branches of the family could be inferred. When the SCA8 repeat tract was evaluated in sperm samples from individuals with expansions of 80 to 800 repeats in leukocytes, contractions to repeat lengths of less than 100 CTGs were observed, a size not often associated with disease. The authors hypothesized that the en masse repeat contractions in sperm may underlie the reduced penetrance associated with paternal transmission.
Day et al. (2000) reported findings from a further study of the large SCA8 family. CTG tracts were longer in affected (mean = 116 CTG repeats) than in unaffected expansion carriers (mean = 90). Quantitative dexterity testing did not detect even subtle signs of ataxia in unaffected expansion carriers. All 21 affected family members inherited an expansion from their mothers. The maternal penetrance bias was consistent with maternal repeat expansions yielding alleles above the pathogenic threshold in the family (more than 107 CTG) and paternal contractions resulting in shorter alleles. Consistent with the reduced penetrance of paternal transmissions, CTG tracts in all or nearly all sperm (84 to 99) were significantly shorter than in the blood (116) of an affected man. The authors concluded that the biologic relationship between repeat length and ataxia indicates that the CTG repeat is directly involved in SCA8 pathogenesis. They noted that diagnostic testing and genetic counseling are complicated by the reduced penetrance, which often makes the inheritance appear recessive or sporadic, and by interfamilial differences in the length of a stable (CTA)n tract preceding the CTG repeat.
Schols et al. (2003) questioned whether the CTG repeat in SCA8 causes ataxia. Analyzing the alleles of 1,262 German patients with ataxia, they concluded that the CTG repeat is a rare polymorphism.
Corral et al. (2005) reported a woman with cerebellar ataxia who had 2 expansions of the SCA8 CTG repeat (111 and 197 repeats). All 9 of her children were unaffected but had inherited greatly expanded alleles from their mother, ranging from 401 to 1,126 repeats. In all 9 cases, the allele inherited from the father was 18 or 19 repeats. By contrast, in 2 additional families in which 3 affected fathers had homozygous expanded CTG repeats, the unaffected children did not inherit additionally expanded repeats. Corral et al. (2005) suggested that the maternal transmission and expansion of the SCA8 CTG allele observed in their family resulted from gene conversion related to female meiosis.
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. In Sca8 mice, genetic loss of Mbnl1 enhanced motor deficits, suggesting that loss of MBNL1 plays a role in SCA8 pathogenesis. In Sca8 mice and SCA8 human brains, 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 dysregulate gene pathways in the brain, similar to the mechanism involved in myotonic dystrophy (DM1; 160900), which is caused by a CTG repeat expansion in the 3-prime UTR region of the DMPK gene (605377) on chromosome 19q13. Daughters et al. (2009) also suggested that the findings may have relevance for other mainly CAG repeat expansion disorders, in which an expanded CTG repeat on the opposite stand may also have toxic effects.
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.
Possible Roles in Other Neurologic Disorders
Vincent et al. (2000) observed large trinucleotide (CTA/CTG) repeat alleles (more than 100 repeats) at 13q21 in 1.25% of patients with various psychiatric disorders compared to 0.7% of healthy controls and none of individuals affected by or with a family history of SCA. The authors concluded that the high frequency of large alleles at this locus is inconsistent with the much rarer occurrence of SCA8.
The observation of large SCA8 alleles in healthy control subjects and nonataxic patients, together with a lack of segregation of the expanded repeat with ataxia in several families, has raised questions about the pathogenic role of the SCA8 expansion. Sobrido et al. (2001) found allele sizes within the proposed pathogenic range in 3 patients with ataxia of unknown etiology, in 2 individuals from pedigrees with either SCA2 or Friedreich ataxia (229300), and in 2 patients with Alzheimer disease. They suggested that sizing of SCA8 alleles should not be a routine diagnostic test until its etiologic role is clarified and the pathogenic threshold determined.
In a study in Italy, Cellini et al. (2001) analyzed material from 167 patients affected by sporadic, autosomal dominant, and autosomal recessive hereditary ataxia for expanded CTA/CTG repeats. They found abnormally expanded repeats in 5 ataxic patients: 3 with pure cerebellar ataxia, 1 with vitamin E deficiency, and 1 sporadic case with gluten ataxia. They concluded that CTG expansions may be linked to SCA8. The patients presented peculiar phenotypic features, suggesting that additional factors may predispose to the disorder. In the patient with expanded SCA8 CTA/CTG triplet repeats and vitamin E deficiency reported by Cellini et al. (2001), Cellini et al. (2002) identified compound heterozygosity for mutations in the TTPA gene (600415.0004 and 600415.0006), yielding a nonfunctional protein. Mutations in the TTPA gene have been associated with Friedreich-like ataxia (AVED; 277460). Clinically, she had progressive ataxia from the age of 7 years, becoming wheelchair bound at age 17, and cerebellar atrophy. Supplementation with vitamin E did not improve symptoms. The authors suggested that the SCA mutations acted in the neurodegenerative process, worsening the neurologic signs caused by the vitamin E deficit.
Topisirovic et al. (2002) studied the length of the SCA8 CTA/CTG expansions (which they called combined repeats, or CRs) in 115 patients with ataxia, 64 unrelated individuals with nontriplet neuromuscular diseases, 70 unrelated patients with schizophrenia, and 125 healthy controls. Only 1 patient with apparently sporadic ataxia was identified with an expansion of 100 CRs, which he had inherited from his asymptomatic father (140 CRs) and transmitted the mutation to his son (92 CRs). Paternal transmission in this family produced contractions of 40 and 8 CRs, respectively. None of the subjects from the other studied groups had an expansion at the SCA8 locus. In the control group, the number of CRs at the SCA8 locus ranged from 14 to 34. The findings supported the hypothesis that allelic variants of the expansion mutation at the SCA8 locus can predispose to ataxia.
Sulek et al. (2003) demonstrated that SCA8 repeat expansion coexists not only with SCA6, but also with SCA1.
Factor et al. (2005) reported a patient with onset of dysarthria and impairment of balance and coordination at age 53 years that rapidly progressed to include gait and postural instability, urinary incontinence, impotence, and depression. MRI showed cerebellar and pontine atrophy. Molecular analysis identified an expansion of 145 CTA/CTG repeats in one allele and 28 repeats in the other allele, which is consistent with SCA8. However, postmortem examination showed findings consistent with multiple system atrophy. Factor et al. (2005) noted that the association between the SCA8 repeat expansion and ataxia is controversial, and suggested that testing sporadic cases with late-onset ataxia may lead to misdiagnosis, as in their case.
Among 75 dominant ataxic independent nuclear families in Spain, Tazon et al. (2002) found 3 with SCA8, representing 4%. A 25-year-old man with a clinical picture of progressive ataxia and dysarthria beginning at age 12 years was homozygous for the expansion of the CTA/CTG 3-prime untranslated region of SCA8. On neurologic examination, he showed ataxia, slight dysarthria, and nystagmus to extreme lateral gaze. Cranial MRI showed global atrophy of cerebellum, but the brainstem was spared. Ataxia had been present in his grandfather and father. His mother, who had no ataxia antecedents in her family, was healthy at age 52; a molecular study of SCA8 revealed 1 allele that could be considered as premutated.
Juvonen et al. (2002) identified SCA8 repeat expansions in 22 of 251 unrelated Finnish SCA patients. They defined alleles with 15 to 40 combined repeats as normal, and those with 80 to 800 as expanded. None of the 22 SCA8-positive patients had expansions at SCA1, 2, 3, 6, 7, 10 (603516), 12 (604326), 17 (607136), DRPLA (607462), or FXN (606829) loci. Thirteen of the patients had a family history of SCA, which was compatible with a dominant inheritance pattern in 9.
Izumi et al. (2003) analyzed the SCA8 CTA/CTG repeat in a large group of Japanese subjects. The frequency of large alleles (85 to 399 CTA/CTG repeats) was 1.9% in spinocerebellar ataxia, 0.4% in Parkinson disease (PD; 168600), 0.3% in Alzheimer disease, and 0% in a healthy control group; the frequency was significantly higher in the group with SCA than in the control group. Homozygotes for large alleles were observed only in the group with SCA. In 5 patients with SCA from 2 families, a large SCA8 CTA/CTG repeat and a large SCA6 (183086; 601011) CAG repeat coexisted. Age at onset was correlated with SCA8 repeats rather than SCA6 repeats in these 5 patients. In 1 of these families, at least 1 patient showed only a large SCA8 CTA/CTG repeat allele, with no large SCA6 CAG repeat allele. Izumi et al. (2003) speculated that the presence of a large SCA8 CTA/CTG repeat allele influences the function of channels such as the alpha-1A-voltage-dependent calcium channel (CACNA1A; 601011), resulting in the development of cerebellar ataxia, especially in homozygous patients. They discussed the possibility that SCA8 works through SCA6 gene products.
In a study in Taiwan, Wu et al. (2004) detected abnormal expansions of trinucleotide repeats in both the SCA8 and SCA17 (607136) genes in patients with Parkinson disease. The clinical presentation of these patients was typical of idiopathic PD with the following characteristics: late onset of disease, resting tremor in the limbs, rigidity, bradykinesia, and a good response to levodopa.
Ikeda et al. (2004) described the molecular genetic features and disease penetrance of 37 families with SCA8 ataxia from the United States, Canada, Japan, and Mexico. SCA8 shows a complex inheritance pattern with extremes of incomplete penetrance, in which often only 1 or 2 affected individuals are found in a given family. By haplotype analysis using 17 short tandem repeat (STR) markers spanning a region of approximately 1 Mb in families with ataxia, as well as a group of expansion carriers in the general population and a group of psychiatric patients, Ikeda et al. (2004) sought to clarify the genetic basis of the reduced penetrance and to investigate whether CTG expansions among different populations share a common ancestral background. Two major ancestrally related haplotypes (A and A-prime) 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. Two additional and distinct haplotypes were found among a group of Japanese families with ataxia (haplotype B) and a Mexican family with ataxia (haplotype C). The findings that SCA8 expansions on 3 independently arising haplotypes are found among patients with ataxia and cosegregate with ataxia when multiple family members are affected further supported the direct role of the CTG expansion in disease pathogenesis.
Martins et al. (2005) performed haplotype and sequencing analysis in a large region encompassing the SCA8 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.
Moseley et al. (2006) reported a transgenic mouse model in which the full-length human SCA8 mutation is transcribed using its endogenous promoter. They found that (CTG)116 expansion, but not (CTG)11 control lines, develop a progressive neurologic phenotype, with in vivo imaging showing reduced cerebellar-cortical inhibition. Both polyleucine- and polyglutamine-containing expansion proteins have been reported to form intranuclear inclusions that are recognized by the 1C2 monoclonal antibody (Zoghbi and Orr, 2000; Dorsman et al., 2002). Moseley et al. (2006) found that 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, ATXN8 (613289), spanning the repeat in the CAG direction. The neurologic phenotype in SCA8 BAC expansion but not BAC control lines demonstrated the pathogenicity of the (CTG-CAG)n expansion. Moreover, the expression of noncoding (CUG)n expansion ATXN8OS transcripts and the discovery of intranuclear polyglutamine inclusions suggested that SCA8 pathogenesis involves toxic gain-of-function mechanisms at both the protein and the RNA levels.
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.
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