Sequence variations in RAN gene as potential modifiers of age at onset of Spinocerebellar Ataxia Type 3/Machado-Joseph disease

• Autor(a) principal: Rangel, Carolina Konrdörfer
• Data de Publicação: 2020
• Tipo de documento: Trabalho de conclusão de curso
• Idioma: eng
• Título da fonte: Repositório Institucional da UFRGS
• Texto Completo: http://hdl.handle.net/10183/252250
• topic: Farmácia; Ataxias espinocerebelares; Doença de Machado-Joseph; Spinocerebellar ataxia type 3; Machado-Joseph disease; RAN gene; Genetic modifiers; PolyQ

Spinocerebellar ataxia type 3 or Machado-Joseph disease (SCA3/MJD) is the most prevalent autosomal dominant hereditary type of ataxia worldwide, causing motor incoordination by progressive neurodegeneration. The disease is due to a CAG trinucleotide expansion at the gene ATXN3 that is inversely correlated to the disease age of onset (AO). This correlation explains about 60% of variation in AO, suggesting that genetic and/or environmental factors may act as modifiers of the disease manifestations. Neuronal intranuclear inclusions (NII) were reported to directly affect the disease progression. Genetic variations in the gene coding for Ran (ras-related nuclear protein), an essential component of the nucleocytoplasmic transport system, can interfere with NII formation and potentially modify the AO. In this study, variants rs14035 and rs7132224 were genotyped in patients of a SCA3/MJD from South Brazil. In addition, linkage disequilibrium (LD) and haplotype reconstruction were assessed, and combined haplotypes correlated to AO. No statistical differences were found between patients and control groups in allelic and genotypic distributions. However, minor allele frequencies were shown to be less represented in SCA3/MJD group for rs14035 and rs7132224 (p=0.081 and p=0.058 respectively, for genotypic distributions). The most frequent haplotype found was AC, followed by GT, corroborating with the LD found. Patients carrying GT/GT combined haplotype have, on average, a delay of 1.8 years in AO (p=0.089). Therefore, our data suggests that the studied RAN variants are involved in genetic modulation of AO in SCA3/MJD, enhancing the requirement for further studies evaluating the relationship between nucleocytoplasmic transport and polyglutaminopathies neurotoxicity.