Browsing by Subject "DNA-mutaatioanalyysi"

Introduction: Parkinson’s disease is the second most common neurodegenerative disease in the Western countries with a prevalence of about 0.3% in the population. Approximately 5 to 10% of patients are estimated to have a hereditary form of the disease. In recent years, 23 gene loci have been found, in which mutations cause hereditary Parkinson’s disease. In Finland, however, only a few disease linked gene variants have been found so far. Aims and methods: To find out if there are gene variants previously found in Parkinson’s disease patients in the Finnish population, we searched variants found in literature search in a novel genetic database, SISu, which contains genetic data of over 10 000 Finns. In addition, to confirm population findings and search for new gene variants, we analyzed 47 patient cohort with a designed gene panel and also another cohort, containing 147 patients, by minisequencing one variant found in the population data. Results: We found 16 variants in five different genes in the population data. Three of them were considered pathogenic and four likely benign after our analysis. In addition, we found nine potentially disease linked variants in eight different patients. Four of the variants were novel. Discussion: Finns seem to carry only few previously described gene variants in genes linked to Parkinson’s disease. It is likely that Finns carry their own unique variants, some of which we also found in our study. Our analysis brings valuable information about the still scarce knowledge of the genetics of this disease in the Finnish population. In addition, we were able to evaluate the disease risk of many variants further by studying their occurrence in Finns. The study of novel gene variants may bring valuable new information about the pathogenic processes related to the disease; especially the location of a novel variant in PARK2 gene found in our study turned out to be crucial for one of the previously suggested disease mechanisms.

Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8+ T-cell clones; in 20% (5/25) of patients CD8+ T cells, but not CD4+ T cells, harbour somatic mutations. In healthy controls (n=20), only one mutation is identified in the CD8+ T-cell pool. Mutations exist exclusively in the expanded CD8+ effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8+ T cells, which may have pathogenic significance for RA and other autoimmune diseases.