Alternative titles; symbols
HGNC Approved Gene Symbol: ATXN10
SNOMEDCT: 715754007;
Cytogenetic location: 22q13.31 Genomic coordinates (GRCh38) : 22:45,671,834-45,845,307 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q13.31 | Spinocerebellar ataxia 10 | 603516 | Autosomal dominant | 3 |
By positional cloning in the spinocerebellar ataxia-10 (SCA10; 603516) candidate region on chromosome 22q13-qter, Matsuura et al. (2000) identified a gene, ataxin-10 (ATXN10), encoding a deduced 475-amino acid protein with 82% identity with a presumed mouse ortholog (E46).
By Northern blot analysis, Wakamiya et al. (2006) identified a 2-kb mRNA ATXN10 transcript.
Matsuura et al. (2000) presented a schematic representation of the structure of the ATXN10 gene, which has 12 exons and spans 172.8 kb of genomic DNA.
The ATXN10 gene maps to chromosome 22q13 (Matsuura et al., 2000).
In all affected patients from 5 Mexican families with spinocerebellar ataxia-10, Matsuura et al. (2000) found an expansion of a pentanucleotide (ATTCT) repeat in intron 9 of the ATXN10 gene (601150.0001).
In affected members of 4 Mexican families with SCA10, Rasmussen et al. (2001) identified expanded ATTCT repeats ranging from 920 to 4,140 repeats.
Fang et al. (2002) reported a 19-year-old Hispanic woman from the U.S. with SCA10 who was found to have a 280-repeat expansion. Her asymptomatic mother had the same expansion. This was the smallest SCA10 expansion mutation identified to date. Alonso et al. (2006) reported a Brazilian family in which the proband had a 400-repeat expansion in the ATXN10 gene. She was a 59-year-old woman with gait ataxia since age 50 years. She also had mild limb ataxia, dysarthria, extensor plantar responses, and moderate axonal peripheral neuropathy. Two unaffected sibs and her unaffected father, aged 65, 56, and 90, had alleles of 370 and 360. In another Brazilian family, the affected son inherited an allele of 750 repeats from his affected mother who had 760 repeats. Alonso et al. (2006) noted that the first family lowered the threshold of repeat numbers for pathogenesis down to 400. Combined with the report of Fang et al. (2002), the findings suggested that there may be reduced penetrance for SCA10 alleles of 280 to 370 repeats.
Wakamiya et al. (2006) detected normal sizes and amounts of ATXN10 mRNA transcripts in multiple cell lines derived from patients with SCA10. SCA10 cell lines showed that the expanded repeat did not interfere with transcription or processing of the ATXN10 gene and also did not affect the transcription of neighboring genes. Wakamiya et al. (2006) concluded that a simple haploinsufficiency, gain-of-function, or neighboring gene effect are unlikely mechanisms contributing to SCA10 and suggested that a transdominant mechanism may be at work.
McFarland et al. (2013) identified 3 different repeat interruptions at the 5- and 3-prime ends of the ATTCT ATXN10 expansion. Two heptanucleotide repeats were found at the 5-prime end and a pentanucleotide repeat was found at the 3-prime end. A specifically designed PCR assay showed that in some cells derived from SCA10 patients, stretches of the pure ATTCT pathogenic repeat were frequently interrupted by combinations of the 3 repeats; the interruptions thus occurred within the pathogenic SCA10-specific repeat. Among 31 SCA10 families tested, the ATXN10 expansion size was larger in patients with an interrupted pathogenic allele. However, there was no difference in the age at onset compared with those expansions without detectable interruptions. An inverse correlation between the expansion size and the age at onset was found only with SCA10 alleles without interruptions. Interrupted expansion alleles showed anticipation but were accompanied by a paradoxical contraction in intergenerational repeat size, and there was evidence of a paternal effect. The findings suggested that SCA10 expansions with ATCCT interruptions differ from SCA10 expansions without detectable ATCCT interruptions in repeat size-instability dynamics and pathogenicity.
Wakamiya et al. (2006) found that Atxn10-null mice died at early postimplantation stage, whereas heterozygous mutants were overtly normal and showed no motor abnormalities. Histologic examination of brain tissue from heterozygous mice also showed no abnormalities.
In all affected members of 5 Mexican families with SCA10 (603516), Matsuura et al. (2000) detected expansion of a pentanucleotide (ATTCT) repeat in intron 9 of the ATXN10 gene. There was an inverse correlation between the expansion size, up to 22.5 kb larger than the normal allele, and the age of onset. Analysis of 562 chromosomes from unaffected individuals of various ethnic origins, including 242 chromosomes from Mexicans, showed a range of 10 to 22 ATTCT repeats with no evidence of expansions. The data indicated that the ATXN10 intronic ATTCT pentanucleotide repeat in SCA10 patients is unstable and represented the largest microsatellite expansion found to that time in the human genome.
In a multigenerational study, Matsuura et al. (2004) demonstrated that (1) the expanded ATTCT repeats are highly unstable when paternally transmitted, whereas maternal transmission results in significantly smaller changes in repeat size; (2) blood leukocytes, lymphoblastoid cells, buccal cells, and sperm have a variable degree of mosaicism in ATTCT expansion; (3) the length of the expanded repeat was not observed to change in individuals over a 5-year period; and (4) clinically determined anticipation is sometimes associated with intergenerational contraction rather than expansion of the ATTCT repeat.
Alonso, I., Jardim, L. B., Artigalas, O., Saraiva-Pereira, M. L., Matsuura, T., Ashizawa, T., Sequeiros, J., Silveira, I. Reduced penetrance of intermediate size alleles in spinocerebellar ataxia type 10. Neurology 66: 1602-1604, 2006. [PubMed: 16717236] [Full Text: https://doi.org/10.1212/01.wnl.0000216266.30177.bb]
Fang, P., Matsuura, T., Teive, H. A. G., Raskin, S., Jayakar, P., Schmitt, E., Ashizawa, T., Roa, B. B. Spinocerebellar ataxia type 10 ATTCT repeat expansions in Brazilian patients and in a patient with early onset ataxia. (Abstract) Am. J. Med. Genet. 71 (suppl.): 552 only, 2002.
Matsuura, T., Fang, P., Lin, X., Khajavi, M., Tsuji, K., Rasmussen, A., Grewal, R. P., Achari, M., Alonso, M. E., Pulst, S. M., Zoghbi, H. Y., Nelson, D. L., Roa, B. B., Ashizawa, T. Somatic and germline instability of the ATTCT repeat in spinocerebellar ataxia type 10. Am. J. Hum. Genet. 74: 1216-1224, 2004. [PubMed: 15127363] [Full Text: https://doi.org/10.1086/421526]
Matsuura, T., Yamagata, T., Burgess, D. L., Rasmussen, A., Grewal, R. P., Watase, K., Khajavi, M., McCall, A. E., Davis, C. F., Zu, L., Achari, M., Pulst, S. M., Alonso, E., Noebels, J. L., Nelson, D. L., Zoghbi, H. Y., Ashizawa, T. Large expansion of the ATTCT pentanucleotide repeat in spinocerebellar ataxia type 10. Nature Genet. 26: 191-194, 2000. [PubMed: 11017075] [Full Text: https://doi.org/10.1038/79911]
McFarland, K. N., Liu, J., Landrian, I., Gao, R., Sarkar, P. S., Raskin, S., Moscovich, M., Gatto, E. M., Teive, H. A. G., Ochoa, A., Rasmussen, A., Ashizawa, T. Paradoxical effects of repeat interruptions on spinocerebellar ataxia type 10 expansions and repeat instability. Europ. J. Hum. Genet. 21: 1272-1276, 2013. [PubMed: 23443018] [Full Text: https://doi.org/10.1038/ejhg.2013.32]
Rasmussen, A., Matsuura, T., Ruano, L., Yescas, P., Ochoa, A., Ashizawa, T., Alonso, E. Clinical and genetic analysis of four Mexican families with spinocerebellar ataxia type 10. Ann. Neurol. 50: 234-239, 2001. [PubMed: 11506407] [Full Text: https://doi.org/10.1002/ana.1081]
Wakamiya, M., Matsuura, T., Liu, Y., Schuster, G. C., Gao, R., Xu, W., Sarkar, P. S., Lin, X., Ashizawa, T. The role of ataxin 10 in the pathogenesis of spinocerebellar ataxia type 10. Neurology 67: 607-613, 2006. [PubMed: 16924013] [Full Text: https://doi.org/10.1212/01.wnl.0000231140.26253.eb]