Calendário de Defesas e Seminários

Data: Quarta-feira, 23 de Outubro de 2019 (12:00 - 23:59)

Investigation of variants in genes of the ataxin-3 cleavage pathway as age at onset modifiers factors in MJD/SCA3 cohort

Orientadora: Dra. Laura Bannach Jardim

Avaliadora:  Dra. Maria Luiza Saraiva Pereira

23 de outubro de 2019 (quarta-feira)


Machado–Joseph disease, also known as spinocerebellar ataxia type 3 (SCA3/MJD), is caused by an expanded CAG (CAGexp) repeat at ATXN3, which translates into a polyglutamine tract (polyQ) within the ataxin-3 protein. SCA3 is the most prevalent form of ataxia in the world, and Rio Grande do Sul (Brazil) is the local with the highest relative frequency, representing 78% of all local spinocerebellar ataxias. Proteolytic cleavage has been proposed as a key event in the molecular pathogenesis of SCA3/MJD. Calpain-mediated proteolysis promotes ataxin-3 translocation to the nucleus, aggregation, cell injury and neurodegeneration; In this work, we aimed to evaluate the relation between AO of SCA3/MJD carriers and single-nucleotide polymorphisms (SNP) in CAPN2 (rs17599) the gene that translates into Calpain-2, and CAST (rs27852 and rs1559085 variants). 240 SCA3/MJD symptomatic subjects whose data on AO was available were included: 125, 32 and 104 subjects were classified as early, average and late onset, respectively. Genotypes of CAPN2 rs17599, CAST rs27852, and CAST rs1559085 did not present different proportions of subgroups AO (ns, chi-square), nor differences in their mean AO (ns, ANOVA). AO distributions were not different when the alleles were analyzed in a dominant model (t-test). However, subjects carrying simultaneously the CC genotype rs27852 and the allele G at rs1559085 in the CAST gene had a mean AO of  38 (±14,29) years, while AO of the remaining subjects was 34 (±13,02) years (p=0.057).These results suggest that a haplotypic conformation of CAST might be related to modulation of SCA3/MJD phenotype - specifically,  C at rs27852 and G at rs1559085 were associated with an almost significant delay in AO. This haplotype might be linked to a functional change in calpastatin, at least in our cohort, ie, to an increased effect of calpastatin over calpain inhibition.

Local  Anfiteatro do Departamento de Genética, Prédio 43312, Campus do Vale/UFRGS
Contato: PPGBM - Av. Bento Gonçalves, 9500 - Prédio 43312 M - Telefone: (51)3308-6722 / E-mail:
por Tamara Moch