Trofimova N. Analysis of biochemical and molecular-genetic changes in families with high risk of mucopolysaccharidosis from Ukraine

The thesis is dedicated to the investigation of the specificities of biochemical diagnostics of mucopolysaccharidoses (MPS) and the study on mutation spectra in genes IDUA and SGSH in Ukrainian patients with MPS and their family members. The thresholds of biological variation for the biochemical markers values, specific for MPS in Ukrainian population, were determined along with the intervals of respective values for the families, suffering from this pathology. The data obtained were used for the purpose of optimizing the interpretation of selective screening results and biochemical diagnostics of MPS. The complete spectrum of rearrangements in IDUA and SGSH genes was determined in patients with MPS I and MPS IIIA, which caused the development of these diseases. It was established that 47% of mutant alleles in IDUA gene in Ukrainian patients with MPS I contained major rearrangements p.Q70* and p.W402*. Three previously non-described missense-mutations - p.N372S, p.Q563P and p.S633* were determined in gene IDUA –their probable impact on the severity of MPS I was analyzed with usage of analysis in silico. It was proven that the incidence of mutation p.R74C in gene SGSH is the highest for the patients with MPS IIIA, amounting to 64.3% (27/42), the missense-mutation p.N389K was found to be ranked the second (7.1%). Three previously non-described mutations – c.216delC, p.G149A and c.1045_1070del27 – were determined in gene SGSH, their probable impact on the functional activity of the gene product was analyzed in silico. The comparative analysis of the incidence of allele variants of the investigated genes was conducted for patients with MPS I and MPS IIIA in Ukraine and other ethnic groups. The study on the specificities of molecular-genetic characteristics of the patients with MPS I and MPS IIIA was used to optimize the algorithms of molecular-genetic analysis for early diagnostics of these diseases.