Mytsyk N. Molecular and genetic characterization of hereditary orphan metabolic disorders,accompanied with beta-galactosidase deficiency

The thesis is dedicated to the study of the specificities of molecular and genetic characterization of diseases, accompanied with beta-galactosidase deficiency, in Ukrainian patients and to the elaboration of the step-wise laboratory examination of persons, belonging to the high-risk group, with the purpose of early and accurate diagnostics of ?-galactosidase deficiency. It was determined that the biological variation thresholds for the ?-galactosidase activity values among the Ukrainian population. The primary beta-galactosidase deficiency was confirmed for 26 patients and secondary deficiency – for one patient, based on the results of determining abnormal fractions of oligosaccharides and the increased excretion of the keratan sulfate in urine and detecting ?-galactosidase activity deficiency in the study group patients. The study of the spectrum of mutations in gene GLB1 in patients with GM1-gangliosidosis (25 patients) and Morquio B disease (1 patient) allowed identifying 52 alleles, containing 17 types of mutations, which conditioned the progress of this disease. The six mutations have not been described in the databases, including two deletions (c.699delG, c.833delG), two missense mutations (p.Gly243Arg, p.Gly262Ala), one – complex mutation (?.[1203_1205delTTA;1207C>A]) and nucleotide replacement in the splicing site (IVS12+8T>C). The high incidence of the missense mutation p.His281Tyr was revealed in gene GLB1 (37 %) among the examined Ukrainian patients with GM1-gangliosidosis. The highest incidence of GM1-gangliosidosis was found in the Transcarpathian region (1:35 080 newborn) and Ivano-Frankivsk region (1:48 871 newborn) with the accumulation of missense mutations p.His281Tyr (74 %) and .Gly255His (100 %) in the patients’ genotypes. The algorithm of laboratory examination of the high risk group patients for the presence of beta-galactosidase deficiency was developed with the introduction of the step of selective screening of major mutation p.His281Tyr in gene GLB1 in Ukrainian patients.