In silico assessment of the possible pathogenetic effect of the missense variant c.441G>A p.(Met147Ile) of the SLC26A4 gene on the function/structure of the pendrin protein using the AlfhаFold neural network algorithm

In this work, for the first time, an in silico evaluation of the possible pathogenic effect of the c.441G>A p.(Met147Ile) variant of uncertain significance of the SLC26A4 gene on the function/structure of the pendrin (SLC26A4) protein was performed using the AlphaFold neural network algorithm, wh...

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Bibliographic Details
Published in:Human Genetics
Main Authors: V. G. Pshennikova, G. P. Romanov, L. A. Klarov, N. A. Barashkov, В. Г. Пшенникова, Г. П. Романов, Л. А. Кларов, Н. А. Барашков
Format: Article in Journal/Newspaper
Language:Russian
Published: Publishing House «Genius Media» LLC 2022
Subjects:
Якутия
missense variant
SLC26A4 gene
pendrin protein (SLC26A4)
AlfhaFold system
Yakutia
миссенс-замена
ген SLC26A4
белок пендрин (SLC26A4)
система AlfhаFold
Якути*
Online Access:https://www.medgen-journal.ru/jour/article/view/2185
https://doi.org/10.25557/2073-7998.2022.06.37-48
Description
Summary:In this work, for the first time, an in silico evaluation of the possible pathogenic effect of the c.441G>A p.(Met147Ile) variant of uncertain significance of the SLC26A4 gene on the function/structure of the pendrin (SLC26A4) protein was performed using the AlphaFold neural network algorithm, which predicts the spatial structure of the protein when such a structure is unknown. Based on the predicted model of the human pendrin tertiary structure, the alignment of the mutant (p.Met147Ile) and native protein structures was carried out using the PyMOL graphics program. As a result, the calculated similarity index of the two structures RMSD (root-mean-square deviation of atomic positions) was less than 2 Å, which indicates that the missense p.(Met147Ile) substitution theoretically does not violate the structural stability of the protein. Probably, the pathogenic effect of the mutation occurs at the functional level, since the analyzed p.(Met147Ile) is located in a critical region of the core domain (an evolutionarily conserved α3-helix region of the TMD), the disruption of which can lead to incorrect substrate transport or the appearance of toxic conformations in the transmembrane region. В работе впервые проведена in silico оценка возможного патогенетического влияния варианта c.441G>A p.(Met147Ile) гена SLC26A4, имеющего в настоящее время статус -вариант неопределенного значения (US - uncertain significance), на функцию/структуру белка пендрина (SLC26A4), выполненного при помощи нейросетевого алгоритма AlphaFold, предсказывающего пространственную структуру белка, когда подобная структура неизвестна. На основе предсказанной модели третичной структуры пендрина человека, было проведено выравнивание мутантной (p.Met147Ile) и нативной структуры белка с помощью графической программы PyMOL. В результате рассчитанный показатель сходства двух структур RMSD (среднеквадратичное отклонение положения атомов) составил меньше 2 Å, то есть миссенс замена p.(Met147Ile) теоретически не нарушает структурную стабильность ...

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