Genetic factors contributing to ALS in Turkey: ATXN2 polyq repeat expansions and SNP/CNV associations

ALS is the most frequent motor neuron disorder and so far no cure has been developed for this devastating disease. ALS is characterized by the selective loss of both the upper motor neurons of the motor cortex and the lower motor neurons extending through the brainstem and spinal cord to skeletal muscle. The majority of ALS patients (86.5-99 per cent) are sporadic and the remaining cases have a reported family history. With more than 25 genes and several loci identified so far, approximately 60 percent of familial and only a small proportion of sporadic ALS cases have been explained. Thus, identification of new genes contributing to disease is crucial. A comprehensive study combining yeast screen, fly/cell biology and human genetics led to the identification of the association of intermediate length (27-33) PolyQ expansions in the ATXN2 gene and ALS risk. In this study, the distribution of ATXN2 PolyQ sizes in a Turkish cohort including 236 patients and 420 healthy controls were investigated. Furthermore, to evaluate other possible genetic associations of this locus with ALS, SNP and haplotypes were analyzed. In addition to SNP and haplotype analyses, validation of candidate CNVs in the MAP4K3, HLA-B and EPHA3 genes, previously found to be disease-associated, was performed. In accordance with other studies, this thesis confirmed that >30 PolyQ repeats in the ATXN2 gene are associated with ALS risk in 1.7% of the Turkish ALS cohort under study. Additionally, a significant association of a 5-SNP haplotype block across the ATXN2 and SH2B3 genes was found in three per cent of the ALS cohort, which was not present in the controls (p = 0.0011). CNV validation studies revealed that EPHA3 is a possible protective factor against ALS in the Turkish ALS cohort under study. EPHA3 is one of the members of receptor tyrosine kinase (RTK) family and ATXN2 and SH2B3 encode proteins that both interact with growth receptor tyrosine kinases. Our novel observation suggests that proteins of RTK pathway and their interaction partners may be promising targets for therapeutic interventions.