16/04 – SEMINÁRIO DE DADOS (Mestrado) – INGRID PAOLA NEVES TUCHTENHAGEN

14/04/2025 • Seminários e Defesas

SEMINÁRIO DE DADOS (Mestrado)

INGRID PAOLA NEVES TUCHTENHAGEN

Effect of variants in DNA repair genes as modifying factors for age of onset in Machado-Joseph Disease

Orientadora: Dra. Laura Bannach Jardim

Avaliadora: Dra. Ursula da Silveira Matte

16 de abril de 2025 (quarta-feira)

12h

Presencial: Anfiteatro do Departamento de Genética da UFRGS (Campus do Vale, prédio 43312)

Abstract

Spinocerebellar Ataxia Type 3 (SCA3/MJD) is the most common form of hereditary ataxia, caused by a CAG repeat expansion in the ATXN3 gene. Although this expansion is strongly associated with age at symptom onset, it accounts for only part of the variability observed among patients. Evidence suggests that variants in DNA repair genes, particularly those in the Mismatch Repair (MMR) pathway, may modulate age at onset by influencing expansion instability. This study investigated the association between variants in seven MMR genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2) and the age at onset of gait ataxia (AOga), also including variants previously implicated in the cohort, such as FAN1 and intermediate CAG alleles in ATXN2. A total of 356 symptomatic individuals from the SCA3/MJD cohort in Rio Grande do Sul, Brazil, were analyzed, all of whom had available clinical and genetic data and stored DNA samples. Genotyping was performed by real-time PCR using TaqMan assays. Associations between variants and AOga were assessed using Linear Mixed Models, controlling for CAG expansion size and family. Significant associations were found for MLH1 (rs1799977), MSH3 (rs2250063), MSH6 (rs1042821), and ATXN2, all linked to delays in AOga ranging from 1.7 to 7.7 years. Variants in MLH3, MSH2, PMS1, and FAN1 showed no association, and the effect of PMS2 could not be evaluated due to lack of genotypic variability. These findings reinforce the modulatory role of genetic variants in DNA repair pathways on the onset of symptoms in SCA3/MJD, contributing to a better understanding of the mechanisms underlying clinical variability in the disease.