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Information × Registration Number 0225U004950, (0121U110054) , R & D reports Title Molecular-genetic mechanisms of human disorders of sexual development popup.stage_title Аналіз первинної структури кодованого мутантного білка та моделювання просторової структури функціональних доменів і, зокрема, домену до якого входить виявлена мутація. Контроль виявлених мутантних варіантів шляхом секвенування за Сенгером продуктів ПЛР, отриманих гна базі ДНК матриці до складу якої входить досліджувані мутантні варіанти. Створення оптимізованого алгоритму біоінформаційної обробки даних повноекзомного секвенування. Head Livshyts Liudmyla A., д.б.н. Registration Date 23-12-2025 Organization Institute of Molecular Biology and Genetics of NAS of Ukraine popup.description1 Identify pathogenic mutations in determinant genes, disorders of which lead to diseases associated with impaired development of sex differentiation. Identify new candidate genes in which mutations are associated with impaired sex differentiation. Develop new effective information tools for the analysis of full-genome sequencing data to effectively assess the pathogenicity of identified genetic variants as a basis for genetic diagnosis and personalized therapy. popup.description2 Results The nature and origin of new genetic variants in known determinant genes that lead to impaired development and differentiation of the genital organs were determined. The molecular nature of pathogenicity for the c.1437A>G mutation in the WT1 gene, which causes splicing disorders, has been identified in a patient with a 46XX karyotype, SRY- and a diagnosis of ovotestis. Showed that this mononucleotide substitution leads to the synthesis of the WT1 protein with the absence of the 4th zinc finger sequence in the DNA-binding domain and causes an aberrant ratio of alternative +CTS/-CTS transcripts, i.e., causes the simultaneous action of two different molecular mechanisms of the pathogenesis of sexual development disorders. In a patient with 46XY, SRY+ and a diagnosis of gonadal dysgenesis (complete form), a missense mutation in the GATA4 gene c.34G>C (p.Gly12Arg) was identified. The results of mutant protein in silico modeling established possible molecular mechanisms of the pathogenesis for sexual development disorders. The phenomenon of incomplete penetrance for mutations in the GATA4 gene was also revealed. A new candidate gene – STARD8(DLC3), mutations in which cause gonadogenesis disorders, was identified. There mutations that disrupt the functioning of the C-terminal in protein Start domain, lead to disorders of testicular development in embryogenesis. It is proposed to include this gene in a specialized diagnostic panel of genes. Identified that the genes encoding the partner proteins STARD9 and CDK5RAP2, in which mutant variants were detected in a patient with a karyotype of 46XY, SRY+ and a diagnosis of a gonadal dysgenesis (complete form), were proposed as new genetic factors of oligogenic sex development disorders and should be included in the specialized diagnostic genetic panel. An algorithm for bioinformatic analysis of the results of whole-exome sequencing at the stage of clinical annotation for patients with orphan diseases was developed. Product Description popup.authors Gorodna Alexsandra Vladimirovna Maryna V. Nechyporenko Hanna B. Livshyts Sirokha Dmytro А. Nataliia M. Kril Oleksandr S. Tarakanov popup.nrat_date 2025-12-23 Close