Year 2019, Volume 7, Issue 3, Pages 1931 - 1946 2019-07-31

TMCO1 Gen Sekans Varyanlatlarının Fonksiyonel Özelliklerinin In Silico Analizlerlerle Değerlendirilmesi
Assessing the Functional Properties of the TMCO1 Sequence Variants by Using In Silico Analyses

Dilek Pirim [1] , Elif Uz-Yıldırım [2] , Niyazi Kaya [3] , Zeynep Kurt [4] , Erva Ulusoy [5]

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Transmembran and Coiled-Coil Domains 1 (TMCO1) proteini, TMCO1 geni tarafından kodlanır ve 7 ekzondan oluşur. Önceki çalışmalar serebrofasiotorasik displazili (SFTD) hastalarda çok sayıda TMCO1 varyantı tanımlamış ve TMCO1 lokusunun primer açık açılı glokom hastalığı ile (PAAG) ilişkili olduğunu göstermiştir. Bununla birlikte TMCO1 gen sekansı varyantlarının ilişkilerini bildiren sınırlı sayıda araştırma vardır ve elde edilen bulguların çoğu anlamsız mutasyonlar ve çerçeve kayması mutasyonlarının TMCO1 varyantlarının patojenliğini ve klinik fenotiplerle ilişkilerini belirtmektedir. Bu nedenle, TMCO1'de aminoasit değişikliklerine neden olan tek nükleotid varyantlarının fonksiyonel özellikleri henüz tam olarak açıklanamamıştır. Bu çalışmada aminoasit değişikliklerinin protein yapısı üzerindeki etkilerini, post-translasyon modifikasyonlardaki (PTM) ve TMCO1 proteini için düzenleyici mekanizmadaki olası rollerini belirledik. Yaygın olarak kullanılan in silico araçları  (SIFT, MutationTaster2, Polyphen2) ile yaptığımız analizin değerlendirmesine göre 41 adet yanlış anlamlı mutasyon barındıran varyantı patojenik olarak sınıflandırdık. Bu 41 varyanttan dördü (p.K211Q, p.K105E, p.S235F, p.K237R) PTM ve düzenleyici protein bağlama bölgelerinde yer almaktadır, bu nedenle bu varyantların fonksiyon üzerinde etkili olduğunu düşündük. Bununla birlikte, rs1387528611 (s.Lys128Gln) varyantının (RegulomeDB skoru= 2b) düzenleyici varyant olabileceğine dair güçlü biyolojik kanıtlar olduğunu saptadık. In silico analizlerimizin sonuçları, TMCO1 ile ilişkili hastalık fenotiplerine katkıda bulunabilecek yanlış anlamlı TMCO1 varyantların fonksiyonel önemini ve insan hastalıklarındaki rollerini ortaya çıkarmak için in vivo değerlendirmenin işlevsel önemini vurgulamaktadır.

Transmembrane and Coiled-Coil Domains 1 (TMCO1) protein is encoded by TMCO1 gene consists of 7 exons. Previous studies have identified multiple TMCO1 variants in patients with cerebro-facio-thoracic dysplasia (CFTD) and TMCO1 locus was also shown to be associated with primary open angle glaucoma (POAG). However, there are limited number of research exist reporting associations of the TMCO1 gene sequence variants and majority of the findings affirm the pathogenicity of the nonsense and frameshift TMCO1 variants and their associations with clinical phenotypes. Thus functional properties of the single nucleotide variants causing amino acid changes in the TMCO1 are yet to be comprehensively elucidated. In this study, we evaluated the effects of amino acid substitutions on protein structure, identified their putative roles in post-translational modifications (PTM) and in regulatory mechanism for TMCO1 protein. We classified 41 missense variants as pathogenic based on combined scores of common in silico tools (SIFT, MutationTaster2, Polyphen2). Of these 41 variants, four (p.K211Q, p.K105E, p.S235F, p.K237R) were identified to be located in PTMs and regulatory protein binding sites; thus they were proposed to be putative functional variants. Moreover, rs1387528611 (p.Lys128Gln) had also strong evidence (RegulomeDB score=2b) for its possible regulatory function. The results of our in silico analyses highlight the functional importance of the missense TMCO1 variants that may contribute to the TMCO1-associated disease phenotypes and further in vivo evaluation yet to be needed to uncover their role in human diseases.

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Primary Language en
Subjects Engineering
Journal Section Articles
Authors

Orcid: 0000-0002-0522-9432
Author: Dilek Pirim (Primary Author)
Institution: Uludag University
Country: Turkey


Orcid: 0000-0002-1459-5485
Author: Elif Uz-Yıldırım (Primary Author)
Institution: Uludag University
Country: Turkey


Orcid: 0000-0002-5122-3824
Author: Niyazi Kaya
Institution: Uludag University

Orcid: 0000-0003-2466-2335
Author: Zeynep Kurt
Institution: Uludag University

Orcid: 0000-0002-2643-0362
Author: Erva Ulusoy
Institution: Uludag University

Dates

Publication Date: July 31, 2019

Bibtex @research article { dubited571528, journal = {Düzce Üniversitesi Bilim ve Teknoloji Dergisi}, issn = {}, eissn = {2148-2446}, address = {Duzce University}, year = {2019}, volume = {7}, pages = {1931 - 1946}, doi = {10.29130/dubited.571528}, title = {Assessing the Functional Properties of the TMCO1 Sequence Variants by Using In Silico Analyses}, key = {cite}, author = {Pirim, Dilek and Uz-Yıldırım, Elif and Kaya, Niyazi and Kurt, Zeynep and Ulusoy, Erva} }
APA Pirim, D , Uz-Yıldırım, E , Kaya, N , Kurt, Z , Ulusoy, E . (2019). Assessing the Functional Properties of the TMCO1 Sequence Variants by Using In Silico Analyses. Düzce Üniversitesi Bilim ve Teknoloji Dergisi, 7 (3), 1931-1946. DOI: 10.29130/dubited.571528
MLA Pirim, D , Uz-Yıldırım, E , Kaya, N , Kurt, Z , Ulusoy, E . "Assessing the Functional Properties of the TMCO1 Sequence Variants by Using In Silico Analyses". Düzce Üniversitesi Bilim ve Teknoloji Dergisi 7 (2019): 1931-1946 <http://dergipark.org.tr/dubited/issue/46290/571528>
Chicago Pirim, D , Uz-Yıldırım, E , Kaya, N , Kurt, Z , Ulusoy, E . "Assessing the Functional Properties of the TMCO1 Sequence Variants by Using In Silico Analyses". Düzce Üniversitesi Bilim ve Teknoloji Dergisi 7 (2019): 1931-1946
RIS TY - JOUR T1 - Assessing the Functional Properties of the TMCO1 Sequence Variants by Using In Silico Analyses AU - Dilek Pirim , Elif Uz-Yıldırım , Niyazi Kaya , Zeynep Kurt , Erva Ulusoy Y1 - 2019 PY - 2019 N1 - doi: 10.29130/dubited.571528 DO - 10.29130/dubited.571528 T2 - Düzce Üniversitesi Bilim ve Teknoloji Dergisi JF - Journal JO - JOR SP - 1931 EP - 1946 VL - 7 IS - 3 SN - -2148-2446 M3 - doi: 10.29130/dubited.571528 UR - https://doi.org/10.29130/dubited.571528 Y2 - 2019 ER -
EndNote %0 Duzce University Journal of Science and Technology Assessing the Functional Properties of the TMCO1 Sequence Variants by Using In Silico Analyses %A Dilek Pirim , Elif Uz-Yıldırım , Niyazi Kaya , Zeynep Kurt , Erva Ulusoy %T Assessing the Functional Properties of the TMCO1 Sequence Variants by Using In Silico Analyses %D 2019 %J Düzce Üniversitesi Bilim ve Teknoloji Dergisi %P -2148-2446 %V 7 %N 3 %R doi: 10.29130/dubited.571528 %U 10.29130/dubited.571528
ISNAD Pirim, Dilek , Uz-Yıldırım, Elif , Kaya, Niyazi , Kurt, Zeynep , Ulusoy, Erva . "Assessing the Functional Properties of the TMCO1 Sequence Variants by Using In Silico Analyses". Düzce Üniversitesi Bilim ve Teknoloji Dergisi 7 / 3 (July 2019): 1931-1946. https://doi.org/10.29130/dubited.571528
AMA Pirim D , Uz-Yıldırım E , Kaya N , Kurt Z , Ulusoy E . Assessing the Functional Properties of the TMCO1 Sequence Variants by Using In Silico Analyses. DUBİTED. 2019; 7(3): 1931-1946.
Vancouver Pirim D , Uz-Yıldırım E , Kaya N , Kurt Z , Ulusoy E . Assessing the Functional Properties of the TMCO1 Sequence Variants by Using In Silico Analyses. Düzce Üniversitesi Bilim ve Teknoloji Dergisi. 2019; 7(3): 1946-1931.