Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease

Akçimen, Fulya; Martins, Sandra; Liao, Calwing; Bourassa, Cynthia V.; Catoire, Hélène; Nicholson, Garth A.; Rieß, Olaf; Raposo, Mafalda; França, Marcondes Cavalcante; Vasconcelos, João; Lima, Manuela; Lopes-Cendes, Íscia; Saraiva-Pereira, Maria Luiza; Jardim, Laura Bannach; Sequeiros, Jorge; Rouleau, Guy A.

doi:10.18632/aging.102825

Cited by 11 publications

(10 citation statements)

References 42 publications

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“…The identification of genetic modifiers holds promise for modulating disease progression. The search for genetic modifiers of polyQ diseases has been actively carried out in the past 8‐13,35 . Most studies have provided only the genetic association without offering validation.…”

Section: Discussionmentioning

confidence: 99%

“…The search for genetic modifiers of polyQ diseases has been actively carried out in the past. [8][9][10][11][12][13]35 Most studies have provided only the genetic association without offering validation. With data obtained from cohorts of patients with HD and SCA3, we herein identify variants of 16 candidate genes that are associated with an AO LTA in both polyQ diseases.…”

Section: Discussionmentioning

confidence: 99%

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A PIAS1 Protective Variant S510G Delays polyQ Disease Onset by Modifying Protein Homeostasis

et al. 2021

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Background Polyglutamine (polyQ) diseases are dominant neurodegenerative diseases caused by an expansion of the polyQ‐encoding CAG repeats in the disease‐causing gene. The length of the CAG repeats is the major determiner of the age at onset (AO) of polyQ diseases, including Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3). Objective We set out to identify common genetic variant(s) that may affect the AO of polyQ diseases. Methods Three hundred thirty‐seven patients with HD or SCA3 were enrolled for targeted sequencing of 583 genes implicated in proteinopathies. In total, 16 genes were identified as containing variants that are associated with late AO of polyQ diseases. For validation, we further investigate the variants of PIAS1 because PIAS1 is an E3 SUMO (small ubiquitin‐like modifier) ligase for huntingtin (HTT), the protein linked to HD. Results Biochemical analyses revealed that the ability of PIAS1S510G to interact with mutant huntingtin (mHTT) was less than that of PIAS1WT, resulting in lower SUMOylation of mHTT and lower accumulation of insoluble mHTT. Genetic knock‐in of PIAS1S510G in a HD mouse model (R6/2) ameliorated several HD‐like deficits (including shortened life spans, poor grip strength and motor coordination) and reduced neuronal accumulation of mHTT. Conclusions Our findings suggest that PIAS1 is a genetic modifier of polyQ diseases. The naturally occurring variant, PIAS1S510G, is associated with late AO in polyQ disease patients and milder disease severity in HD mice. Our study highlights the possibility of targeting PIAS1 or pathways governing protein homeostasis as a disease‐modifying approach for treating patients with HD. © 2021 International Parkinson and Movement Disorder Society

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A PIAS1 Protective Variant S510G Delays polyQ Disease Onset by Modifying Protein Homeostasis

et al. 2021

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“…As with other repeat expansion disorders (Depienne and Mandel 2021), measured repeat length is inversely correlated to age at onset accounting for ~ 55 to 60% of the variation in disease severity (de Mattos et al 2019;Akcimen et al 2020). The ATXN3 repeat is complex with the reference sequence (NM_004993.6) incorporating two synonymous glutamine-encoding CAA variants at positions three and six, and a nonsynonymous lysine-encoding AAG variant at position four i.e., (CAG)2(CAA)1(AAG)1(CAG)1(CAA)1(CAG)x (Kawaguchi et al 1994;Igarashi et al 1996) (Figure 1).…”

Section: Introductionmentioning

confidence: 75%

“…As with other repeat expansion disorders (Depienne and Mandel 2021), measured repeat length is inversely correlated to age at onset accounting for ∼ 55 to 60% of the variation in disease severity (de Mattos et al . 2019; Akcimen et al . 2020).…”

Section: Introductionmentioning

confidence: 99%

Age-dependent somatic expansion of theATXN3CAG repeat in the blood and buccal cell DNA of individuals with spinocerebellar ataxia type 3

Sidky,

Melo,

Kay

et al. 2024

Preprint

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Spinocerebellar ataxia type 3 (SCA3), a currently untreatable disorder, is caused by the expansion of a genetically unstable polyglutamine-encoding complex CAG repeat in the ATXN3 gene. Longer alleles are generally associated with earlier onset and frequent intergenerational expansions mediate the anticipation observed in this disorder. Somatic expansion of the repeat has also been implicated in disease progression and slowing the rate of somatic expansion in patients has recently been proposed as a therapeutic strategy. Here, we utilised high-throughput ultra-deep MiSeq amplicon sequencing of the ATXN3 repeat to precisely define the number of repeats, the exact sequence structure, the phased genotype of an adjacent single nucleotide polymorphism and to accurately quantify somatic expansion in blood and buccal cell DNA samples of a cohort of individuals with SCA3 from the Azores islands (Portugal). We revealed systematic mis-sizing of the ATXN3 repeat and high levels of inaccuracy of the traditional fragment length analysis approach that have important implications for attempts to identify modifiers of clinical and molecular phenotypes, including genetic instability. Quantification of somatic expansion in blood DNA revealed the expected effects of age and CAG repeat length, although the effect of repeat length was surprisingly modest with much stronger associations with age at sampling. We also observed an association of the downstream rs12895357 single nucleotide polymorphism with the rate of somatic expansion, and a higher level of somatic expansion in buccal cell DNA compared to blood. Although the levels of somatic expansion are much lower per repeat unit, the average level of somatic expansion at the ATXN3 locus in SCA3 patients is much higher than is typically observed at the HTT locus in Huntington disease patients. These data suggest that the ATXN3 locus in SCA3 patients in blood or buccal cell DNA might serve as a good biomarker for clinical trials testing suppressors of somatic expansion with peripheral exposure.

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“…In addition, GWAS Catalog database has reported that PQBP5/NOL10 was associated with cardiac troponin levels, arterial stiffness, waist circumference, and liver fibrosis, but not with polyQ diseases (https:// www.ebi.ac.uk/gwas/genes/NOL10), although it is unclear whether 46,231 human SNPs linked to PQBP5/NOL10 gene (https://www.ncbi. nlm.nih.gov/snp/?term=NOL10) have been examined in previous GWAS studies of polyQ diseases [35][36][37][38] . Expression profile databases such as Expression Atlas (https://www.ebi.ac.uk/gxa/home) have shown that PQBP5/NOL10 is widely distributed in human/mouse neural and nonneural cells, tissues, and organs.…”

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confidence: 99%

PQBP5/NOL10 maintains and anchors the nucleolus under physiological and osmotic stress conditions

et al. 2023

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Polyglutamine binding protein 5 (PQBP5), also called nucleolar protein 10 (NOL10), binds to polyglutamine tract sequences and is expressed in the nucleolus. Using dynamic imaging of high-speed atomic force microscopy, we show that PQBP5/NOL10 is an intrinsically disordered protein. Super-resolution microscopy and correlative light and electron microscopy method show that PQBP5/NOL10 makes up the skeletal structure of the nucleolus, constituting the granule meshwork in the granular component area, which is distinct from other nucleolar substructures, such as the fibrillar center and dense fibrillar component. In contrast to other nucleolar proteins, which disperse to the nucleoplasm under osmotic stress conditions, PQBP5/NOL10 remains in the nucleolus and functions as an anchor for reassembly of other nucleolar proteins. Droplet and thermal shift assays show that the biophysical features of PQBP5/NOL10 remain stable under stress conditions, explaining the spatial role of this protein. PQBP5/NOL10 can be functionally depleted by sequestration with polyglutamine disease proteins in vitro and in vivo, leading to the pathological deformity or disappearance of the nucleolus. Taken together, these findings indicate that PQBP5/NOL10 is an essential protein needed to maintain the structure of the nucleolus.

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Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease

Cited by 11 publications

References 42 publications

A PIAS1 Protective Variant S510G Delays polyQ Disease Onset by Modifying Protein Homeostasis

A PIAS1 Protective Variant S510G Delays polyQ Disease Onset by Modifying Protein Homeostasis

Age-dependent somatic expansion of theATXN3CAG repeat in the blood and buccal cell DNA of individuals with spinocerebellar ataxia type 3

PQBP5/NOL10 maintains and anchors the nucleolus under physiological and osmotic stress conditions

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