Relevance of epigenetics in the pathogenic mechanism of spinocerebellar ataxia type 37

• Autor(a) principal: Figueiredo, Ana Sofia Tavares
• Data de Publicação: 2020
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/111133
• topic: Neurodegenerative diseases; repeat instability; Single Nucleotide Polymorphisms (SNPs); DNA methylation; Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias

Spinocerebellar ataxia 37 (SCA37) is an autosomal-dominant neurodegenerative disease characterized by cerebellar atrophy, gait and limb incoordination, and dysarthria as the first symptom. SCA37 is caused by an (ATTTC)n insertion within a nonpathogenic (ATTTT)n located in a 5’ UTR intron of DAB1. The age of onset in patients correlates with the number of ATTTCs and there is an increase in repeat insertion size during transmission to the next generation, with larger increases when the father is the transmitting parent. Haplotype analysis suggested that genetic factors flanking the mutant allele act as cis-elements influencing repeat instability. To identify cis-elements of genetic instability involved in the origin of mutant SCA37 chromosomes, we investigated single nucleotide polymorphisms (SNPs) and methylation status in the SCA37 repeat flanking region. SNPs were assessed by Sanger sequencing and DNA methylation by bisulfite sequencing of chromosomes containing nonpathogenic (ATTTT)<50, (ATTTT)>50 and interrupted, and mutant SCA37 alleles. We found a total of nine SNPs and confirmed that the repeat flanking region is highly polymorphic. SNP 7 and SNP 9 were present in all nonpathogenic large, interrupted and mutant SCA37 alleles studied, whereas only a small number of short nonpathogenic chromosomes carried these SNPs; they were associated with an increase in the (ATTTT)n tract, suggesting they might be a factor for repeat instability. These two SNPs are both in CpG dinucleotides, causing their elimination. The location of these SNPs shows an above average occupancy score for CTCF-binding in several cancer and embryonic human cells, which reinforces their involvement in repeat instability. In conclusion, this work allowed the identification of genetic variants that could have modified the epigenetics of the DAB1 (ATTTT)n flanking region and led to repeat instability. The occurrence of variants in important cis-regulatory elements might have created the ideal conditions for the mutational mechanism, originating the SCA37 (ATTTC)n insertion.