medecolМедицина и экологияMedicine and ecology2305-60452305-6053Карагандинский медицинский университет10.59598/ME-2305-6053-2026-118-1-125-133medecol-1319Research ArticleТЕОРЕТИЧЕСКАЯ И ЭКСПЕРИМЕНТАЛЬНАЯ МЕДИЦИНАTHEORETICAL AND EXPERIMENTAL MEDICINEIn silico анализ редких патогенных миссенс-вариантов гена SLC6A2In silico analysis of rare pathogenic missense variants in the SLC6A2 geneСорокинаМ. А.SorokinaM. A.

100008, г. Караганда, ул. Гоголя 40

100008, Karaganda c., 40 Gogolya str., 40

info@qmu.kzКоршуковИ. В.KorshukovI. V.

Илья Васильевич Коршуков

100008, г. Караганда, ул. Гоголя 40

Ilya Vasilyevich Korshukov

100008, Karaganda c., 40 Gogolya str., 40

Korshukov@qmu.kzТурсынбекА. Е.TursynbekA. E.

100008, г. Караганда, ул. Гоголя 40

100008, Karaganda c., 40 Gogolya str., 40

info@qmu.kzИнститут наук о жизни, кафедра информатики и биостатистики НАО «Карагандинский медицинский университет»КазахстанInstitute of Life Sciences, Department of Informatics and Biostatistics, Karaganda Medical University NC JSCKazakhstan20260507202601125133Copyright © Сорокина М.А., Коршуков И.В., Турсынбек А.Е., 20262026Сорокина М.А., Коршуков И.В., Турсынбек А.Е.Sorokina M.A., Korshukov I.V., Tursynbek A.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://medecol.qmu.kz/jour/article/view/1319Актуальность

Актуальность. Натрий-зависимый транспортер норадреналина (NET), кодируемый геном SLC6A2, играет ключевую роль в регуляции норадренергической передачи и ассоциирован с ортостатической непереносимостью, синдромом дефицита внимания и гиперактивности (СДВГ), депрессией и автономными нарушениями. Появление крио-ЭМ структур NET человека в комплексе с норадреналином и антидепрессантами, а также новых алгоритмов машинного обучения открыло возможность систематического in silico скрининга известных миссенс-вариантов гена и выявления ранее не охарактеризованных патогенных замен, которые могут объяснять случаи идиопатической ортостатической непереносимости, резистентной депрессии, парадоксального ответа на терапию или наследуемых автономных расстройств.

Цель

Цель. Анализ миссенс-вариантов гена SLC6A2, зарегистрированных в базе NCBI (сборка GRCh38.p14), выделение вариант с наивысшими предсказаниями патогенности и их структурно- функциональных характеристика с использованием современных биоинформатических инструментов.

Материалы и методы

Материалы и методы. Из 725 миссенс однунклеотидных вариантов (ОНВ) с неизвестной клинической значимостью для гена SLC6A2 (GRCh38) были отобраны биаллельные варианты с наибольшими оценками патогенности (AlphaMissense ≥0,99 и LIST-S2 ≥0,99). Два редких варианта (rs1397308523 (Pro108Thr) и rs759975667 (p.Gln314Arg) были подвергнуты комплексному in silico анализу.

Результаты и обсуждение

Результаты и обсуждение. Оба замещаемых остатка высококонсервативны (ConSurf 9/9). Прогноз топологии (DeepTMHMM) и доменной организации (PROSITE) не выявил различий с диким типом. MutPred2 оценил общую патогенность в 0,87 и 0,91 соответственно. I-Mutant 2.0 и MUpro предсказали снижение стабильности белка (ΔΔG –1,11 и –0,94 ккал/моль).

Выводы

Выводы. Варианты rs1397308523 и rs759975667, имеющие наибольшую прогнозируемую патогенность, миссенс-замены в SLC6A2 представляют приоритетные мишени для функциональных исследований и поиска в клинических когортах.

Background

Background. The sodium-dependent noradrenaline transporter (NET), encoded by the SLC6A2 gene, plays a key role in the regulation of noradrenergic transmission and is associated with orthostatic intolerance, attention-deficit/hyperactivity disorder (ADHD), depression, and autonomic dysfunctions. The emergence of cryo-EM structures of human NET in complex with noradrenaline and antidepressants, along with new machine-learning algorithms, has enabled systematic in silico screening of known missense variants of the gene and the identification of previously uncharacterized pathogenic substitutions that may explain cases of idiopathic orthostatic intolerance, treatment-resistant depression, paradoxical responses to therapy, or hereditary autonomic disorders.

Aim of the study was to analyze missense variants of the SLC6A2 gene registered in the NCBI database (assembly GRCh38.p14), to identify variants with the highest predicted pathogenicity scores, and to perform their structural-functional characterization using modern bioinformatics tools.

Materials and methods

Materials and methods. From 725 missense single-nucleotide variants (SNVs) of unknown clinical significance in the SLC6A2 gene (GRCh38), biallelic variants with the highest pathogenicity scores (AlphaMissense ≥0.99 and LIST-S2 ≥0.99) were selected. Two rare variants (rs1397308523 (Pro108Thr) and rs759975667 (p.Gln314Arg) underwent comprehensive in silico analysis.

Results and discussion

Results and discussion. Both substituted residues are highly conserved (ConSurf 9/9). Predictions of topology (DeepTMHMM) and domain organization (PROSITE) revealed no differences from the wild type. MutPred2 assigned overall pathogenicity scores of 0.87 and 0.91, respectively. I-Mutant 2.0 and MUpro predicted decreased protein stability (ΔΔG –1.11 and –0.94 kcal/mol).

Conclusions

Conclusions. The variants rs1397308523 and rs759975667, which have the highest predicted pathogenicity among missense substitutions in SLC6A2, represent priority targets for functional studies and screening in clinical cohorts.

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The authors declare that there are no conflicts of interest present.