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ATXN2, (CAG)n EXPANSION, INTERMEDIATE AND Amyotrophic lateral sclerosis 13

Significance: risk factor
ClinVar: RCV000008583

Variant: ATXN2, (CAG)n EXPANSION, INTERMEDIATE

Type: Variant
Allele: ATXN2, (CAG)n EXPANSION, INTERMEDIATE 23153
Gene:
Type: Microsatellite
References: OMIM: 601517.0002

Condition

Disease: Amyotrophic lateral sclerosis 13

Citations

    The findings of Elden et al. (2010) were replicated in 2 independent studies by Daoud et al. (2011) and Van Damme et al. (2011), who studied French, French Canadian, and Belgian populations. Each study identified an association between development of ALS and high-length ATXN2 repeat alleles (29 or more repeats), using receiver operating characteristic curve analysis of patients and controls. Neither study found a correlation between size of repeat and disease parameters. Moreover, each study found ALS patients with expansion sizes in the range of SCA2 (greater than 32 repeats), and none had features of SCA2 such as cerebellar or brainstem atrophy. The findings indicated a genetic overlap between SCA2 and ALS13.
PMID:20740007
    Among 915 patients with amyotrophic lateral sclerosis, Elden et al. (2010) identified 43 (4.7%) with expansions of the ATXN2 polyQ repeat of intermediate length, 27 through 33 repeats (ALS13; 183090). Among a neurologically normal control cohort of 980 individuals, similar expansions were detected in only 14 (1.4%) individuals (p = 3.6 x 10(-5), odds ratio, 2.80, 95% CI, 1.54-5.12). Elden et al. (2010) analyzed ATXN2 protein levels in patient-derived lymphoblastoid cells from ALS cases harboring intermediate-length polyQ expansions, ALS cases with normal-range repeat lengths, and controls. These studies showed that whereas the steady state levels of ATXN2 were comparable, cycloheximide treatment, which blocks new protein synthesis, revealed an increase in stability (or decreased degradation) of ATXN2 in cells with intermediate-length polyQ repeats. Elden et al. (2010) then found that polyQ expansions in ATXN2 enhance its interaction with TDP43 (605078). Both ATXN2 and TDP43 relocalize to stress granules, sites of RNA processing, under various stress situations such as heat shock and oxidative stress. Under normal conditions TDP43 localized to the nucleus and ATXN2 to the cytoplasm in both control cells and cells harboring polyQ repeat expansions. Elden et al. (2010) proposed that intermediate-length ATXN2 polyQ repeats might confer genetic risk for ALS by making TDP43 more prone to mislocalize from the nucleus to the cytoplasm under situations of stress.
PMID:20740007
    Corrado et al. (2011) identified intermediate expansion of the CAG repeat (greater than 30 repeats) in exon 1 of the ATXN2 gene in 7 (3.0%) of 232 Italian patients with ALS. None of 395 controls had an allele larger than 30 repeats. Four of the 7 patients had an allele in the intermediate-fully pathologic range: 1 with 32 repeats, 2 with 33 repeats, and 1 with 37 repeats, accounting for 1.7% of the ALS cohort. Sequencing of these fully expanded alleles showed that they were all interrupted with at least one CAA triplet. The phenotype of the patients was typical of ALS with no signs or symptoms of ataxia or parkinsonism.
PMID:21537950
    The findings of Elden et al. (2010) were replicated in 2 independent studies by Daoud et al. (2011) and Van Damme et al. (2011), who studied French, French Canadian, and Belgian populations. Each study identified an association between development of ALS and high-length ATXN2 repeat alleles (29 or more repeats), using receiver operating characteristic curve analysis of patients and controls. Neither study found a correlation between size of repeat and disease parameters. Moreover, each study found ALS patients with expansion sizes in the range of SCA2 (greater than 32 repeats), and none had features of SCA2 such as cerebellar or brainstem atrophy. The findings indicated a genetic overlap between SCA2 and ALS13.
PMID:21562247
    Among 3,919 patients with various neurodegenerative diseases, including 532 with ALS, 641 with frontotemporal dementia (FTD; 600274), 1,530 with Alzheimer disease (AD; 104300), 702 with Parkinson disease (PD; 168600), and 514 with progressive supranuclear palsy (PSP; see 601104), and 4,877 healthy controls, Ross et al. (2011) found that ATXN2 repeat lengths greater than 30 units were significantly associated with ALS (odds ratio of 5.57; p = 0.001) and with PSP (OR of 5.83; p = 0.004). Repeat expansions were found in 8 (1.5%) ALS patients, 4 (0.8%) PSP patients, and 9 (0.2%) controls. Significant associations between repeats greater than 30 were not observed in patients with FTD, AD, or PD. The findings of expanded repeat alleles (31 to 33) in control individuals indicated that caution should be taken when attributing specific disease phenotypes to these repeat lengths. However, 6 of the controls with expanded repeats were under the mean onset age of all patient groups except PD. The findings confirmed the role of ATXN2 as an important risk factor for ALS and suggested that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.
PMID:21610160
    The findings of Elden et al. (2010) were replicated in 2 independent studies by Daoud et al. (2011) and Van Damme et al. (2011), who studied French, French Canadian, and Belgian populations. Each study identified an association between development of ALS and high-length ATXN2 repeat alleles (29 or more repeats), using receiver operating characteristic curve analysis of patients and controls. Neither study found a correlation between size of repeat and disease parameters. Moreover, each study found ALS patients with expansion sizes in the range of SCA2 (greater than 32 repeats), and none had features of SCA2 such as cerebellar or brainstem atrophy. The findings indicated a genetic overlap between SCA2 and ALS13.
PMID:21670397