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. 2025 Apr;62(4):4854-4865.
doi: 10.1007/s12035-024-04600-y. Epub 2024 Nov 4.

Mutation Screening of ATXN1, ATXN2, and ATXN3 in Amyotrophic Lateral Sclerosis

Tianmi Yang  1 , Qianqian Wei  1 , Dejiang Pang  1 , Yangfan Cheng  1 , Jingxuan Huang  1 , Junyu Lin  1 , Yi Xiao  1 , Qirui Jiang  1 , Shichan Wang  1 , Chunyu Li  2 , Huifang Shang  3
Affiliations

Mutation Screening of ATXN1, ATXN2, and ATXN3 in Amyotrophic Lateral Sclerosis

Tianmi Yang et al. Mol Neurobiol. 2025 Apr.

Abstract

Emerging evidence suggests potential disease modifying roles of ATXN1, ATXN2, and ATXN3 in amyotrophic lateral sclerosis (ALS). We aimed to provide a comprehensive variants profile of the ATXN1, ATXN2, and ATXN3 genes and examine the association of these variants with the risk and clinical characteristics of ALS. We screened and analyzed the rare variants in a cohort of 2220 ALS patients from Southwest China, using controls from the Genome Aggregation Database (gnomAD) and the China Metabolic Analytics Project (ChinaMAP). The over-representation of rare variants and their association with disease risk in ALS patients were assessed using Fisher's exact test with Bonferroni correction at both allele and gene levels. Kaplan-Meier analysis was employed to explore the relationship between the distribution of variants and survival. A total of 62 eligible rare missense variants were identified, comprising 32 from ATXN1, 21 from ATXN2, and 9 from ATXN3. Allelic association testing revealed a significant enrichment of the ATXN1 (c.2122C > G, p.Leu708Val) variant and the ATXN2 (c.3778C > G, p.Pro1260Ala) variant in ALS. Gene burden analysis indicated that variants in the ATXN1 and ATXN3 genes had a higher burden in ALS. Substantial heterogeneity in survival time was observed among patients carrying different variants within the same gene. However, there were no significant differences in survival between ALS patients grouped by N-terminal or C-terminal distribution. Our results provided a genetic variation profile of ATXN1, ATXN2, and ATXN3 in ALS patients, along with the clinical characteristics of individuals carrying these variations. This information might offer valuable insights for the ongoing ALS disease-modifying treatments.

Keywords: ATXN1; ATXN2; ATXN3; Amyotrophic lateral sclerosis; Risk; Survival.

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Conflict of interest statement

Declarations. Ethics Approval: Ethics approval for the study was approved by the institutional ethics committee of Sichuan University. Consent to Participate: Written informed consent was obtained from each participant or their primary caregiver. Consent to Publication: Not applicable. Competing Interests: The authors declare no competing interests.

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