Integrated Bioinformatic Approach for Precision Medicine: Prediction of Human GABRG2 Gene Pathogenic Variants, Characterized with Cellular Pathology and Epilepsy Phenotype Severity

Nabaa Khudhair Abdullah; Ayla Arslan

doi:10.19113/sdufenbed.1394695

Araştırma Makalesi

Integrated Bioinformatic Approach for Precision Medicine: Prediction of Human GABRG2 Gene Pathogenic Variants, Characterized with Cellular Pathology and Epilepsy Phenotype Severity

Yıl 2024, Cilt: 28 Sayı: 3, 300 - 315, 23.12.2024

Nabaa Khudhair Abdullah , Ayla Arslan

https://doi.org/10.19113/sdufenbed.1394695

Öz

Interpreting GABRG2 variants of unknown significance hinders epilepsy precision medicine. Using computer algorithms, our study focused on 156 GABRG2 variants from ClinVar, identifying 10 highly pathogenic variants within the γ2 subunit. Integration with patient mutations and mutagenesis studies locates variants within epileptogenic structural cassettes, aiding phenotype severity and cellular pathology characterization. Our results predict milder phenotypes for 3 N-terminus extracellular domain variants and more severe phenotypes for 7 transmembrane domain variants, linked to cellular pathology with reduced cell surface expression and current. Notably, 4 transmembrane domain variants may distort channel conductance. Our research aligns with ACMG/AMP criteria PP3 and PM1.

Anahtar Kelimeler

GABA (A) receptor, In silico, Epilepsy, Pathogenic variant, Gamma-2 subunit, Precision medicine

Kaynakça

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Hassas Tıp için Bütünleşik Biyoinformatik Yaklaşım: İnsan GABRG2 Geninin Hücre Patolojisi ve Epilepsi Fenotip Şiddeti ile Karakterize Patojenik Varyantlarının Tahmini

Yıl 2024, Cilt: 28 Sayı: 3, 300 - 315, 23.12.2024

Nabaa Khudhair Abdullah , Ayla Arslan

https://doi.org/10.19113/sdufenbed.1394695

Öz

GABRG2 genindeki belirsiz anlam varyantların yorumlanması, epilepsi hassas tıpı için kritik önem teşkil etmektedir. Çalışmamız, ClinVar veri tabanındaki 156 GABRG2 belirsiz anlam varyantına odaklanarak, γ2 alt biriminde 10 patojenik varyantı belirledi. Hasta mutasyonları ve mutagenez çalışmalarıyla entegrasyon sonucunda varyantların epileptojenik yapısal kasetler içinde konumlandırılmasıyla, fenotip şiddeti ve hücresel patoloji karakterize edildi. 3 tane N-terminus ekstrasellüler bölge varyantı daha az şiddetli ve 7 tane transmembran bölge varyantı daha şiddetli epilepsi fenotipleri ile eksilmiş hücre yüzeyi ifadesi ve akımla bağlantılı olarak öngörüldü. Özellikle, 4 transmembran bölge varyantının kanal iletkenliğini bozabileceği belirlendi. Araştırmamız, ACMG/AMP kriterleri PP3 ve PM1 ile uyumludur.

Anahtar Kelimeler

Epilepsi, In siliko, Patojenik varyant, GABA (A) reseptörü, Hassas Tıp, Gama-2 alt birimi

Kaynakça

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[113] Yang Y, Niu X, Cheng M, Zeng Q, Deng J, Tian X, Wang Y, Yu J, Shi W, Wu W, Ma J, Li Y, Yang X, Zhang X, Jia T, Yang Z, Liao J, Sun Y, Zheng H, Sun S and Zhang Y 2022 Phenotypic Spectrum and Prognosis of Epilepsy Patients With GABRG2 Variants Front. Mol. Neurosci. 15 809163
[114] Zou F, McWalter K, Schmidt L, Decker A, Picker J D, Lincoln S, Sweetser D A, Briere L C, Harini C, Undiagnosed Diseases Network M, Marsh E, Medne L, Wang R Y, Leydiker K, Mower A, Visser G, Cuppen I, Gassen K L, Smagt J, Yousaf A and McKnight D 2017 Expanding the phenotypic spectrum of GABRG2 variants: a recurrent GABRG2 missense variant associated with a severe phenotype J. Neurogenet. 31 30–6
[115] Hernandez C C and Macdonald R L 2019 A structural look at GABAA receptor mutations linked to epilepsy syndromes Brain Res. 1714 234–47
[116] Mele M, Costa R O and Duarte C B 2019 Alterations in GABAA-Receptor Trafficking and Synaptic Dysfunction in Brain Disorders Front. Cell. Neurosci. 13 77
[117] Arslan A 2023 Pathogenic variants of human GABRA1 gene associated with epilepsy: A computational approach Heliyon 9
[118] Köhler S, Gargano M, Matentzoglu N, Carmody L C, Lewis-Smith D, Vasilevsky N A, Danis D, Balagura G, Baynam G, Brower A M, Callahan T J, Chute C G, Est J L, Galer P D, Ganesan S, Griese M, Haimel M, Pazmandi J, Hanauer M, Harris N L and Robinson P N 2021 The Human Phenotype Ontology in 2021 Nucleic Acids Res. 49 1207–17
[119] Rácz, A., Galvis-Montes, D. S., Borger, V., Becker, A. J., & Pitsch, J. 2024 Focused review: Clinico-neuropathological aspects of late onset epilepsies: Pathogenesis. Seizure, S1059-1311(24)00182-1.
[120] Trowbridge, S., Poduri, A., & Olson, H. 2021 Early diagnosis and experimental treatment with fenfluramine via the Investigational New Drug mechanism in a boy with Dravet syndrome and recurrent status epilepticus. Epileptic Disord. Int. Epilepsy J. Videotape 954–6

Toplam 120 adet kaynakça vardır.

Ayrıntılar

Birincil Dil	İngilizce
Konular	Bitki Bilimi (Diğer)
Bölüm	Makaleler
Yazarlar	Nabaa Khudhair Abdullah 0000-0003-1785-0522 Ayla Arslan 0000-0002-3119-101X
Yayımlanma Tarihi	23 Aralık 2024
Gönderilme Tarihi	22 Kasım 2023
Kabul Tarihi	30 Ağustos 2024
Yayımlandığı Sayı	Yıl 2024 Cilt: 28 Sayı: 3

Kaynak Göster

APA	Khudhair Abdullah, N., & Arslan, A. (2024). Integrated Bioinformatic Approach for Precision Medicine: Prediction of Human GABRG2 Gene Pathogenic Variants, Characterized with Cellular Pathology and Epilepsy Phenotype Severity. Süleyman Demirel Üniversitesi Fen Bilimleri Enstitüsü Dergisi, 28(3), 300-315. https://doi.org/10.19113/sdufenbed.1394695
AMA	Khudhair Abdullah N, Arslan A. Integrated Bioinformatic Approach for Precision Medicine: Prediction of Human GABRG2 Gene Pathogenic Variants, Characterized with Cellular Pathology and Epilepsy Phenotype Severity. Süleyman Demirel Üniv. Fen Bilim. Enst. Derg. Aralık 2024;28(3):300-315. doi:10.19113/sdufenbed.1394695
Chicago	Khudhair Abdullah, Nabaa, ve Ayla Arslan. “Integrated Bioinformatic Approach for Precision Medicine: Prediction of Human GABRG2 Gene Pathogenic Variants, Characterized With Cellular Pathology and Epilepsy Phenotype Severity”. Süleyman Demirel Üniversitesi Fen Bilimleri Enstitüsü Dergisi 28, sy. 3 (Aralık 2024): 300-315. https://doi.org/10.19113/sdufenbed.1394695.
EndNote	Khudhair Abdullah N, Arslan A (01 Aralık 2024) Integrated Bioinformatic Approach for Precision Medicine: Prediction of Human GABRG2 Gene Pathogenic Variants, Characterized with Cellular Pathology and Epilepsy Phenotype Severity. Süleyman Demirel Üniversitesi Fen Bilimleri Enstitüsü Dergisi 28 3 300–315.
IEEE	N. Khudhair Abdullah ve A. Arslan, “Integrated Bioinformatic Approach for Precision Medicine: Prediction of Human GABRG2 Gene Pathogenic Variants, Characterized with Cellular Pathology and Epilepsy Phenotype Severity”, Süleyman Demirel Üniv. Fen Bilim. Enst. Derg., c. 28, sy. 3, ss. 300–315, 2024, doi: 10.19113/sdufenbed.1394695.
ISNAD	Khudhair Abdullah, Nabaa - Arslan, Ayla. “Integrated Bioinformatic Approach for Precision Medicine: Prediction of Human GABRG2 Gene Pathogenic Variants, Characterized With Cellular Pathology and Epilepsy Phenotype Severity”. Süleyman Demirel Üniversitesi Fen Bilimleri Enstitüsü Dergisi 28/3 (Aralık 2024), 300-315. https://doi.org/10.19113/sdufenbed.1394695.
JAMA	Khudhair Abdullah N, Arslan A. Integrated Bioinformatic Approach for Precision Medicine: Prediction of Human GABRG2 Gene Pathogenic Variants, Characterized with Cellular Pathology and Epilepsy Phenotype Severity. Süleyman Demirel Üniv. Fen Bilim. Enst. Derg. 2024;28:300–315.
MLA	Khudhair Abdullah, Nabaa ve Ayla Arslan. “Integrated Bioinformatic Approach for Precision Medicine: Prediction of Human GABRG2 Gene Pathogenic Variants, Characterized With Cellular Pathology and Epilepsy Phenotype Severity”. Süleyman Demirel Üniversitesi Fen Bilimleri Enstitüsü Dergisi, c. 28, sy. 3, 2024, ss. 300-15, doi:10.19113/sdufenbed.1394695.
Vancouver	Khudhair Abdullah N, Arslan A. Integrated Bioinformatic Approach for Precision Medicine: Prediction of Human GABRG2 Gene Pathogenic Variants, Characterized with Cellular Pathology and Epilepsy Phenotype Severity. Süleyman Demirel Üniv. Fen Bilim. Enst. Derg. 2024;28(3):300-15.

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