Russian Journal of Clinical Ophthalmology
ISSN 2311-7729 (Print), 2619-1571 (Online)

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

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DOI: 10.32364/2311-7729-2019-19-4-180-188

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.



Funding

Autonomous non-commercial organization Laboratory “Sensor technology for deafblind” and Deaf-Blind Support Foundation “Con-nection”.


About the authors:

1Marianna E. Ivanova — MD, PhD, Head of CRO, ORCID iD 0000-0002-1089-4293;

2Dmitry S. Atarshchikov — MD, PhD, ophthalmologist, ORCID iD 0000-0003-4401-9099;

3Andrey M. Demchinsky — MD, PhD, Head of Medical Projects, ORCID iD 0000-0002-1689-9394;

4Vladimir V. Strelnikov — PhD, Head of Epigenetics Laboratory, ORCID iD 0000-0001-9283-902X;

5Debmalya Barh — PhD, Head of R&D Department, ORCID iD 0000-0002-2557-7768;

6Gennadiy V. Poryadin — MD, PhD, Professor, Corresponding Member of RAS, Honorary Head of Pathophysiology Department, ORCID iD 0000-0003-2010-3296;

7Larisa M. Balashova — MD, PhD, Professor, Head of the Center, ORCID iD 0000-0001-9349-7092;

6Jean M. Salmasi — MD, PhD, Professor, Head of Pathophysiology Department, ORCID iD 0000-0001-8524-0019.

1LLC “Oftalmic”. 47/3–3, Leningradsky Prospekt, Moscow,125167, Russian Federation.

2Central Clinical Hospital for Presidential Affairs. 15, Marshala Timoshenko str., Moscow,121359, Russian Federation.

3Autonomous nonprofit organization “Scientific and industrial laboratory “Sensor technology for deafblind”. 2, bld. 3, Paveletskaya naberezhnaya, Moscow, 115114, Russian Federation.

4Research Centre for Medical Genetics. 1, Moskvorechie str., Moscow, 115478, Russian Federation.

5Institute of Integrative Omics and Applied Biotechnology. 209, Cholanayakanahalli str., Bangalore, 560032, India.

6Pirogov Russian National Research Medical University. 1, Ostrovityanov str., Moscow, 117513, Russian Federation.

7Non-profit partnership International Scientific and Practical Center for the Proliferation of Tissues of Russia. 29/14, Prechistenka str., Moscow, 119034, Russian Federation.

Contact information: Marianna E. Ivanova, e-mail: info@oftalmic.ru. Financial Disclosure: Marianna E. Ivanova is the collaborator of LLC “Oftalmic”. Other authors declare that there is no conflict of interests. Received 07.05.2019.




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