MOLECULAR STRUCTURE OF AMYOTROPHIC LATERAL SCLEROSIS IN RUSSIAN POPULATION

Abstract

Materials and methods. 285 Russian patients with amyotrophic lateral sclerosis (ALS) including 260 patients with a sporadic form and 25 with a familial form were examined for mutations in SOD1, C9orf72, TARDBP, ANG and other genes and the presence of associations among polymorphic sites in ATXN2 (polyCAG) and VEGF (-2578С/А) genes. Molecular genetic analysis was performed using direct sequencing, fragment analysis and real-time polymerase chain reaction. On the last stage, rare ALS candidate genes were evaluated using a next generation sequencing (NGS) panel. Results. Total rate of the identified mutations in the examined ALS cohort was 9.5 %. The most frequently observed defects were mutations in the SOD1 (24.0 % in familial ALS and 4.6 % in sporadic ALS) and C9orf72 (pathological hexanucleotide repeat expansion was identified in 1.8 % cases of ALS, all sporadic) genes. The TARDBP gene didn’t contain any mutations, though in the ALS group deletion c.715-126delG located in intron 5 of the TARDBP gene was significantly over-represented – 38.0 % vs. 26.6 % (χ 2 = 13.17; р = 0.002). Mutations in the ANG gene were identified in 1.05 % of ALS patients (all cases were sporadic). In 1 (0.35 %) sporadic case a G1082A mutation in the DCTN1 gene was identified. The examined group significantly more frequently carried a risk allele of the ATXN2 gene with an “intermediate” (28–33) number of CAG repeats – 5.0 % vs. 1.7 % in the control group (χ 2 = 3.89; р = 0.0486). In Russian ALS patients, an association between the disease and the presence of a risk А-allele and homozygote genotype А/А of -2578С/А polymorphism in the VEGF gene was identified (χ 2 = 7.14; р = 0.008 and χ 2 = 13.46; р = 0.001 for the rates in the ALS population and in the control population, respectively), which is confirmed by the odds ratio. Conclusion. In the current article, molecular structure of ALS in the Russian population was examined, rates of individual genetic forms and mutation spectrum were established. This work is of considerable significance for medical genetic counseling and prevention of the disease in the affected families.