The study of interactome in Russian patients with Usher syndrome to select priority approaches in pathogenetically oriented treatment

Abstract

M.E. Ivanova1, D.S. Atarshchikov2, A.M. Demchinsky3, V.V. Strelnikov4, D. Barh5, G.V. Poryadin6, L.M. Balashova7, J.M. Salmasi6 1LLC “Oftalmic”, Moscow, Russian Federation 2Central Clinical Hospital under Presidential Affairs, Moscow, Russian Federation 3Autonomous nonprofit organization “Scientific and industrial laboratory “Sensor technology   for deafblind”, Moscow, Russian Federation 4Research Centre for Medical Genetics, Moscow, Russian Federation 5Institute of Integrative Omics and Applied Biotechnology (IIOAB), Bangalore, India 6Pirogov Russian National Research Medical University, Moscow, Russian Federation 7Non-profit partnership International Scientific and Practical Center for the Proliferation of Tissues of Russia, Moscow, Russian Federation Background: Usher syndrome (USH) is a heterogeneous syndrome characterized by hearing loss and vision loss. The prevalence of USH is estimated to 5:100,000. USH is classified into three subtypes (I, II, and III) depending on the specific gene mutation, i.e., MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2 for type 1; USH2A, ADGRV1, DFNB31 for type 2; and CLRN1 for type 3. USH requires genetic studies to confirm the diagnosis, to manage patients, and to develop pathogenetically oriented treatment approaches. Historical aspects and development of molecular diagnosis of the disease, as well as evolution of approaches to the treatment are discussed. Aim: to study mutational spectrum in a cohort of Russian patients with USH and to analyze metabolome and interactome as well as pathogenic pathways of USH development to discover targeted therapies. Patients and Methods: 28 patients with USH were enrolled in the study and underwent examinations (clinical trial protocol No. NCT03319524 ). Comprehensive eye and ENT examination as well genetic studies were performed. The diagnosis was confirmed by MLPA next-generation sequencing and Sanger sequencing. Results: type 1 USH was diagnosed in 53.57% of patients and type 2 USH in 39.2% of patients. 17.85% were not confirmed genetically being in line with world statistics. Mutations in genes MYO7A (72.72%), CDH23 (9.09%), PCDH15 (9.09%), and USH1C (9.09%) were found in 11 patients. 11 mutations were identified in MYO7A gene, 54.54% were pathogenic mutations described for the first time. MYO7A: p.Q18* was the most common (27.27%) mutation associated with early and the most severe clinical manifestations. Two novel mutations (p.E1301* и c.158-?_318+?del) were identified in PCDH15 gene. In 90% of patients with type 2 USH, the diagnosis was confirmed genetically. 11 mutations were identified in USH2A gene, 27% were pathogenic causative mutations described for the first time. The most common mutations in USH2A were p.W3955* (50%), p.E767fs, p.R1653*, and c.8682–9A>G (20% each). Conclusion: detailed in silico analysis of metabolome and interactome as well as pathogenic pathways of USH development in Russian cohort was performed. The most promising treatment strategies including gene therapy are discussed. Keywords: USH, USH2A, MYO7A, mutation, Usher syndrome, congenital deaf-blindness, gene therapy, interactome, modeling. For citation: Ivanova M.E., Atarshchikov D.S., Demchinsky A.M. et al. The study of interactome in Russian patients with Usher syndrome to select priority approaches in pathogenetically oriented treatment. Russian Journal of Clinical Ophthalmology. 2019;19(4):180–188.