Tretjak B. Spectrum of mutations with hereditary neuromuscular disease in humans example of population in Western Ukraine

The thesis is devoted to study the molecular and genetic background of neuromuscular diseases in humans. Studies of main genes involved in neuromuscular diseases were supplemented with the study of insulin-like growth factor-II gene with emphasis on genetically determined preconditions of its expression at various stages of human ontogenesis in normal and pathological conditions. Mutations in genes involved in the development of neuromuscular diseases were detected in 89 families using methods of molecular genetics. In 20 % of patients with clinically diagnosed Duchenne and Becker muscular dystrophy dystrophin gene deletions were detected. Among 150 examined patients with clinically established diagnosis of spinal muscular atrophy (SMA) there were 37 %) cases in which the diagnosis was confirmed by molecular genetic methods. In 80 % of patients with severe SMA (type I and II) the combination of homozygous deletions of SMN1 gene and 5th exon of NAIP gene was observed. For the first time in Ukraine number of major CAPN3 gene mutations was detected. Namely, 4 carriers of CAPN3 gene mutations. As result, it was established 7% of patients with idiopathic progressive muscular atrophy carry CAPN3 gene mutations. Locus Apa-1 of gene that codes for insulin-like growth factor 2 was analyzed as possible epigenetic factor in the groups of patients with muscular dystrophies and of patients with spontaneous miscarriages. Calculation of odds ratio (OR) shows that the presence of "АG" genotype increases the incidence of muscular dystrophy for more than twice (OR=2.3359). "АG" genotype provokes the disease while "GG" genotype of Apa-1 locus of IGF-ІІ gene protects from the onset of the dystrophy. The 140 spontaneous miscarried human embryos of 5-8 weeks of development were examined, while presence of "АG" genotype SNPApa-1 of insulin-like growth factor 2 increases the risk of embryo elimination more than sevenfold (OR=7.7239). We propose to include the studies of epigenetic factor Apa-1 and IGF-II gene polymorphism to the common protocol for detection of mutations in reference genes during molecular and genetic studies of neuromuscular diseases and their preconditions.