Genetische Grundlagen der Dystonie in türkischstämmigen Familien
Molekulare und zelluläre Neurologie und Neuropathologie
Zusammenfassung der Projektergebnisse
This is the first study in the literature that has uncovered the genetic basis of AR and sporadic families from Turkish population with dystonia or associated clinical pictures using combination of genetic screening strategies. Utilizing this comprehensive approach, we either established the causative role of the identified variants or provided CEN-, animal-research, PPI- or literature-based evidences for the pathogenicity of the candidate genes. Through our unbiased analysis approach, we could genetically characterize 48 Turkish dystonia families. Furthermore, in order to aid in the prospective gene discovery approaches, a list of candidate genes with CEN-, PPI-, animal-research- or GSEO-based supporting evidences for the pathogenicity were generated. Our analysis showed and confirmed that dystonia is genetically and clinically highly heterogeneous group of disorders. Even though our study cohort consisted of only recessive or sporadic forms of the disease from a particular geographical region where recessive forms are common due to the high rate of consanguinity, our analysis revealed a wide spectrum of genetic underpinnings, including known common or uncommon forms of the disease. With the advent of the next generation sequencing techniques, substantial number of dominantly inherited genes has been associated with dystonia. However, very limited number of recessively inherited genes (HPCA, MECR, COL6A3) could be discovered due to the rarity as well as the clinical heterogeneity of the AR dystonia. So far, of those genes, only HPCA could be confirmed by independent studies. Since it is highly challenging to replicate the candidate gene findings in particular geographic origins, to aid in the further gene discovery approaches we generated a list of plausible candidate genes with systems-biology-based evidences identified in a clinically-well-characterized Turkish dystonia cohort. On the basis of the findings of 28 candidate genes, we generated significant CEN modules (black, turquoise, brown, blue) in BG region, identified over-represented pathways and gene ontologies specific for the identified modules, specified particular PPIs in the networks, and lastly, associated animal-model-research- and literature-based information with all the evidences supporting the role of those genes in the dystonia pathogenesis. In conclusion, herein in this study for the first time in the literature we have uncovered the genetic basis of AR or sporadic dystonia families from Turkey. Using stepwise comprehensive genetic screening strategies we could not only genetically and clinically characterize the families with PVs in the known dystonia associated genes, and also provided a list of candidate genes with CEN-, animal-research, PPI- or literature-based evidences for the pathogenicity of dystonia.
