A Novel Duplication in ATXN2 as Modifier for Spinocerebellar Ataxia 3 (SCA3) and C9ORF72‐ALS

Background The ataxin‐2 (ATXN2) gene contains a cytosine‐adenine‐guanine repeat sequence ranging from 13 to 31 repeats, but when surpassing certain thresholds causes neurodegeneration. Genetic alterations in ATXN2 other than pathological cytosine adenine guanine (CAG) repeats are unknown. Methods/Re...

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Bibliographic Details
Published in:Movement disorders 2021-02, Vol.36 (2), p.508-514
Main Authors: Laffita‐Mesa, Jose Miguel, Nennesmo, Inger, Paucar, Martin, Svenningsson, Per
Format: Article
Language:English
Subjects:
Adenine
Alleles
Amyotrophic Lateral Sclerosis
Ataxia
Ataxin
Ataxin-2 - genetics
ATXN2
Basal ganglia
Brief Report
C9ORF72
C9orf72 Protein
Central nervous system diseases
Cytosine
gene modifier
genotype–phenotype correlations
Guanine
Humans
Machado-Joseph Disease
Movement disorders
Neurodegeneration
Neurodegenerative diseases
Parkinson's disease
Polyglutamine
Regular Issue
SCA3
Trinucleotide repeats
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Summary:Background The ataxin‐2 (ATXN2) gene contains a cytosine‐adenine‐guanine repeat sequence ranging from 13 to 31 repeats, but when surpassing certain thresholds causes neurodegeneration. Genetic alterations in ATXN2 other than pathological cytosine adenine guanine (CAG) repeats are unknown. Methods/Results We have identified a 9–base pair duplication in the 2‐gene ATXN2 sense/antisense region. The duplication was found in a Swedish family with spinocerebellar ataxia 3 with parkinsonism, conferring a deviated age at onset unexplained by the concomitant presence of ATXN2 intermediate alleles. Similarly, C9ORF72 amyotrophic lateral sclerosis cases bearing the same duplication had earlier age at onset than those with C9ORF72 and ATXN2 intermediate alleles. No effect was evident in Parkinson's disease (PD) cases without known PD gene mutations. Conclusions We describe the first genetic alteration other than the known intermediate‐range CAG repeats in ATXN2. This 9–base pair duplication may act as an additional hit among carriers of pathological nucleotide expansions in ATXN3 and C9ORF72 with ATXN2 intermediate. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
ISSN:0885-3185
1531-8257
DOI:10.1002/mds.28334