(CAG)
            <sub>n</sub>
            loci as genetic modifiers of age-at-onset in patients with Machado-Joseph disease from mainland China

Zhao, Chunxia; Zheng, Caifa; Long, Zhe; Cao, Li; Li, Xunhua; Shang, Huifang; Yin, Xinzhen; Zhang, Baorong; Liu, Jingyu; Ding, Dacheng; Peng, Yun; Wang, Chunrong; Peng, Hongxia; Ye, Wei; Qiu, Rong; Pan, Qian; Xia, Kun; Chen, Shengdi; Sequeiros, Jorge; Ashizawa, Tetsuo; Klockgether, Thomas; Tang, Beisha; Jiang, Hong

doi:10.1093/brain/aww087

Cited by 38 publications

(51 citation statements)

References 9 publications

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“…Choice of statistical modelling might further evidence how populational differences in CAGexp can impact AO determination. Significant increase in explanation of AO variability was detected in Han Chinese,8 European carriers from non-Portuguese populations and Americans6 using quadratic models. Here, the quadratic modelling of CAGexp from IPDs yielded only a marginal improvement when compared with a simpler, linear regression modelling of AO variance.…”

Section: Discussionmentioning

confidence: 94%

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Genetic risk factors for modulation of age at onset in Machado-Joseph disease/spinocerebellar ataxia type 3: a systematic review and meta-analysis

Mattos

Musskopf²,

Leotti

et al. 2018

J Neurol Neurosurg Psychiatry

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ObjectivesTo perform a systematic review and meta-analysis of genetic risk factors for age at onset (AO) in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD).MethodsTwo authors independently reviewed reports on the mathematical relationship between CAG length at the expanded ATXN3 allele (CAGexp), and other genetic variants if available, and AO. Publications from January 1994 to September 2017 in English, Portuguese or Spanish and indexed in MEDLINE (PubMed), LILACS or EMBASE were considered. Inclusion criteria were reports with >20 SCA3/MJD carriers with molecular diagnosis performed by capillary electrophoresis. Non-overlapping cohorts were determined on contact with corresponding authors. A detailed analysis protocol was registered at the PROSPERO database prior to data extraction (CRD42017073071).ResultsEleven studies were eligible for meta-analysis, comprising 10 individual-participant (n=2099 subjects) and two aggregated data cohorts. On average, CAGexp explained 55.2% (95% CI 50.8 to 59.0; p<0.001) of AO variability. Population-specific factors accounted for 8.3% of AO variance. Cohorts clustered into distinct geographic groups, evidencing significantly earlier AO in non-Portuguese Europeans than in Portuguese/South Brazilians with similar CAGexp lengths. Presence of intermediate ATXN2 alleles (27–33 CAG repeats) significantly correlated with earlier AO. Familial factors accounted for ~10% of AO variability. CAGexp, origin, family effects and CAG length at ATXN2 together explained 73.5% of AO variance.ConclusionsCurrent evidence supports genetic modulation of AO in SCA3/MJD by CAGexp, ATXN2 and family-specific and population-specific factors. Future studies should take these into account in the search for new genetic modifiers of AO, which could be of therapeutic relevance.

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Section: Discussionmentioning

confidence: 94%

“…However, since we did not have access to IPD from the large Chinese cohort that reported the associations between AO and CACNA1A and ATXN7 ,8 population-specific differences in the range of CAG tracts at these loci—and in power to detect their potential effects—should not be overruled.…”

Section: Discussionmentioning

confidence: 99%

Genetic risk factors for modulation of age at onset in Machado-Joseph disease/spinocerebellar ataxia type 3: a systematic review and meta-analysis

Mattos

Musskopf²,

Leotti

et al. 2018

J Neurol Neurosurg Psychiatry

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“…polyQ expansion of ATXN2 has also recently been linked to the age-at-onset of a neurodegenerative disease closely related to ALS/SCA2, known as spinocerebellar ataxia type III (SCA3) or Machado-Joseph’s disease (MJD) [112,113,114]. Three studies have linked the length of the ATXN2 polyQ tract to age-at-onset of MJD, such that intermediate-length alleles correspond to an earlier age-at-onset in both European and Chinese cohorts [112,113,114].…”

Section: Insights Into Atxn2 Roles From Human Disease-focused Studiesmentioning

confidence: 99%

“…Three studies have linked the length of the ATXN2 polyQ tract to age-at-onset of MJD, such that intermediate-length alleles correspond to an earlier age-at-onset in both European and Chinese cohorts [112,113,114]. This points to potentially overlapping pathogenic mechanisms in ALS and MJD.…”

Section: Insights Into Atxn2 Roles From Human Disease-focused Studiesmentioning

confidence: 99%

Ataxin-2: From RNA Control to Human Health and Disease

Ostrowski

Hall

Mekhail

2017

Genes

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RNA-binding proteins play fundamental roles in the regulation of molecular processes critical to cellular and organismal homeostasis. Recent studies have identified the RNA-binding protein Ataxin-2 as a genetic determinant or risk factor for various diseases including spinocerebellar ataxia type II (SCA2) and amyotrophic lateral sclerosis (ALS), amongst others. Here, we first discuss the increasingly wide-ranging molecular functions of Ataxin-2, from the regulation of RNA stability and translation to the repression of deleterious accumulation of the RNA-DNA hybrid-harbouring R-loop structures. We also highlight the broader physiological roles of Ataxin-2 such as in the regulation of cellular metabolism and circadian rhythms. Finally, we discuss insight from clinically focused studies to shed light on the impact of molecular and physiological roles of Ataxin-2 in various human diseases. We anticipate that deciphering the fundamental functions of Ataxin-2 will uncover unique approaches to help cure or control debilitating and lethal human diseases.

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“…3 Since 1991, a new molecular mechanism responsible for several neurogenetic disorders was found, legitimizing anticipation in several diseases such as myotonic dystrophy type 1 (DM1). [10][11][12] Repeat size in the ATXN2, atrophin 1 (ATN1), and huntingtin (HTT) genes, interacting with ATXN3, may modulate AO in Machado-Joseph disease (MJD/SCA3). Previous studies showed that an intermediatelength (CAG) n expansion in the coding region of the ataxin-2 (ATXN2) gene, responsible for spinocerebellar ataxia type 2 (SCA2), was a major contributor to amyotrophic lateral sclerosis (ALS).…”

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confidence: 99%

Large normal alleles of ATXN2 decrease age at onset in transthyretin familial amyloid polyneuropathy Val30Met patients

Santos

Coelho

Alves‐Ferreira

et al. 2019

Annals of Neurology

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Objective: Transthyretin (TTR)-related familial amyloid polyneuropathy (FAP) is an autosomal dominant neurological disease, caused most frequently by a Val30Met (now classified as Val50Met) substitution in TTR. Age at onset (AO) ranges from 19 to 82 years, and variability exists mostly between generations. Unstable oligonucleotide repeats in various genes are the mechanism behind several neurological diseases, found also to act as modifiers for other disorders. Our aim was to investigate whether large normal repeat alleles of 10 genes had a possible modifier effect in AO in Portuguese TTR-FAP Val30Met families. Methods: We analyzed 329 Portuguese patients from 123 families. Repeat length (at ATXN1, ATXN2, ATXN3, ATXN7, TBP, ATN1, HTT, JPH3, AR, and DMPK) was assessed by single and multiplex polymerase chain reaction, using fluorescently labeled primers, followed by capillary electrophoresis. We used a family-centered approach, and generalized estimating equations were used to account for AO correlation between family members. Results: For ATXN2, the presence of at least 1 allele longer than 22 CAGs was significantly associated with an earlier onset in TTR-FAP Val30Met, decreasing mean AO by 6 years (95% confidence interval = −8.81 to −2.19, p = 0.001). No association was found for the remaining repeat loci. Interpretation: Length of normal repeats at ATXN2 may modify AO in TTR-FAP Val30Met and may function as a risk factor. This can be due to the role of ATXN2 in RNA metabolism and as a modulator of various cellular processes, including mitochondrial stress. This may have relevant implications for prognosis and the follow-up of presymptomatic carriers.

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(CAG) _n loci as genetic modifiers of age-at-onset in patients with Machado-Joseph disease from mainland China

Cited by 38 publications

References 9 publications

Genetic risk factors for modulation of age at onset in Machado-Joseph disease/spinocerebellar ataxia type 3: a systematic review and meta-analysis

Genetic risk factors for modulation of age at onset in Machado-Joseph disease/spinocerebellar ataxia type 3: a systematic review and meta-analysis

Ataxin-2: From RNA Control to Human Health and Disease

Large normal alleles of ATXN2 decrease age at onset in transthyretin familial amyloid polyneuropathy Val30Met patients

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(CAG) n loci as genetic modifiers of age-at-onset in patients with Machado-Joseph disease from mainland China

Cited by 38 publications

References 9 publications

Genetic risk factors for modulation of age at onset in Machado-Joseph disease/spinocerebellar ataxia type 3: a systematic review and meta-analysis

Genetic risk factors for modulation of age at onset in Machado-Joseph disease/spinocerebellar ataxia type 3: a systematic review and meta-analysis

Ataxin-2: From RNA Control to Human Health and Disease

Large normal alleles of ATXN2 decrease age at onset in transthyretin familial amyloid polyneuropathy Val30Met patients

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Product

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(CAG) _n loci as genetic modifiers of age-at-onset in patients with Machado-Joseph disease from mainland China