Genetic reports abstractATXN2 intermediate repeat expansions influence the clinical phenotype in frontotemporal dementia
Introduction
Several studies showed that frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of the same clinical, genetic, and pathologic continuum (Van Langenhove et al., 2012). Indeed, these two disorders have a shared genetic background with genes causing either one or the other condition. In both diseases, beyond Mendelian inherited forms, the great majority of cases underlay complex pattern of inheritance; the combination of multiple gene variants acts as predisposing factors, also behaving as genetic modifiers, able to modulate the clinical phenotype.
The boundary between causative and modifiers genes is often blurry, as exemplified by the ATXN2 gene. A number of polyglutamine-encoding CAG triplets above 34 cause spinocerebellar ataxia type 2 (Pulst et al., 1996). However, intermediate repeat expansions (27-33 CAG repeats) in ATXN2 gene have been reported as a genetic risk factor or phenotype modifier in ALS (Elden et al., 2010, Lu et al., 2015). Conversely, the potential role of ATXN2 gene repeats in FTD has been scarcely investigated (Ross et al., 2011, Lattante et al., 2015).
Interestingly, the CAG tract can be pure or interrupted by the presence of CAA repeats. Both CAG and CAA encode for glutamine, but CAAs are known to stabilize the repeat and avoid expansions at somatic and germinal level. CAA interruptions have been identified in intermediate alleles both in healthy and ALS patients but are lost in spinocerebellar ataxia type 2–associated alleles (Tsai et al., 2004, Yu et al., 2011).
Thus, the aim of this study was to evaluate the role of ATXN2 CAG repeats in Italian patients with frontotemporal dementia.
Section snippets
Methods
We measured the number of CAG repeats in exon 1 of the ATXN2 gene (NM_002973.3) by polymerase chain reaction amplification and fluorescent fragment analysis by capillary electrophoresis (ABI Prism 3730xl, Applied Biosystems) in 368 FTD patients (188 males, 180 females; mean age ± SD: 65.8 ± 9.3 years), attending the Department of Neuroscience, University of Torino. Three hundred forty-two healthy subjects were included as controls. Written informed consent was obtained from all participants,
Results
The distribution of the ATXN2 CAG repeats in FTD patients and controls is shown in Fig. 1. The repeat length ranged from 14 to 32 repeats in FTD, and from 14 to 30 repeat units in controls, with 22 repeats being the most common allele. We did not find any fully expanded ATXN2 allele. An intermediate repeat expansion was found in 18 of 368 (4.9%) FTD patients and in 8 of 342 (2.3%) controls. No significant difference in the frequency of intermediate CAG expansions in ATXN2 was found between
Discussion
Our study confirms previous reports suggesting that CAG intermediate repeats in the ATXN2 gene are not likely to be associated with frontotemporal dementia. However, a detailed clinical evaluation allowed us uncovering that intermediate-length repeats may influence the clinical features of the disease. In our data set, carriers of intermediate repeats had a younger age at onset and increased frequency of parkinsonism and psychotic symptoms at the onset of the disease. This suggests that even if
Disclosure statement
None of the authors has any conflict of interest to disclose.
Acknowledgements
This study was supported by Ministero dell'Istruzione, dell'Università e della Ricerca–MIUR project “Dipartimenti di Eccellenza 2018–2022” to Department of Neuroscience “Rita Levi Montalcini”, University of Torino, and AIRAlzh Onlus-ANCC-COOP (SB).
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2021, Neurobiology of DiseaseCitation Excerpt :In model organisms such as yeast, flies and mice it was shown that ATXN2 depletion by genetic knockout or mRNA-knockdown protects against the neurotoxicity of TDP43, which causes motor neuron degeneration in ALS and in FTLD. In addition, patient studies showed genetic ATXN2 variants to contribute to the risk of ALS/FTLD (Becker et al., 2017; Elden et al., 2010; Gispert et al., 2012; Lahut et al., 2012; Lee et al., 2011; Rubino et al., 2019). Although the molecular mechanisms of ALS/FTLD are not understood, the crucial role of RNA toxicity in its pathogenesis became plain upon the identification of various ALS/FTLD disease genes, such as the RNA binding proteins TDP43 (encoded by the TARDBP gene), FUS, HNRNPA2B1, the RNA-particle transporting KIF5A, the RNA toxicity sensor RIPK1, and other stress response factors such as GRN and SOD1 (Taylor et al., 2016).
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2021, Neurobiology of AgingCitation Excerpt :Different studies have tried to identify genetic modifiers of disease risk and phenotypes in FTD, such as the age at onset or survival after onset. For instance, it has been described that ATXN2 intermediate expansion alleles were disease modifiers in FTD C9orf72 expansion carriers (Rubino et al., 2019; van Blitterswijk et al., 2014). A common polymorphism in the 3′UTR of PGRN, rs5848, has been related to the survival after onset in C9orf72 expansion carriers (van Blitterswijk et al., 2014).
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2020, Neurobiology of AgingCitation Excerpt :The presence of IAs in the ATXN2 gene has been associated with an increased risk of developing ALS (Conforti et al., 2012; Elden, 2010; Lee et al., 2011; Sproviero et al., 2017), but no significant association was found between ALS and IAs in HTT (Lee et al., 2011; Ramos et al., 2012). The frequency of IAs in ATXN2 did not differ between patients with FTD and healthy controls (Ross et al., 2011; van Blitterswijk et al., 2014a, b), but these ATXN2 alleles could act as modifiers of the FTD phenotype among carriers and noncarriers of the C9orf72 expansion (Lattante et al., 2014; Rubino et al., 2019). The intermediate C9orf72 expansion has been associated with a risk effect in familial and sporadic FTD (Benussi et al., 2014; van der Zee et al., 2013).
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These authors equally contributed to the article.