TY  - JOUR
T1  - Assessing the Functional Properties of the TMCO1 Sequence Variants by Using In Silico Analyses
TT  - TMCO1 Gen Sekans Varyanlatlarının Fonksiyonel Özelliklerinin In Silico Analizlerlerle Değerlendirilmesi
AU  - Pirim, Dilek
AU  - Uz-yıldırım, Elif
AU  - Ulusoy, Erva
AU  - Kurt, Zeynep
AU  - Kaya, Niyazi
PY  - 2019
DA  - July
DO  - 10.29130/dubited.571528
JF  - Duzce University Journal of Science and Technology
JO  - DÜBİTED
PB  - Duzce University
WT  - DergiPark
SN  - 2148-2446
SP  - 1931
EP  - 1946
VL  - 7
IS  - 3
LA  - en
AB  - Transmembraneand Coiled-Coil Domains 1 (TMCO1) protein is encoded by TMCO1 gene consists of 7 exons. Previous studies have identifiedmultiple TMCO1 variants in patientswith cerebro-facio-thoracic dysplasia (CFTD) and TMCO1 locus was also shown to be associated with primary open angleglaucoma (POAG). However, there are limited number of research exist reportingassociations of the TMCO1 genesequence variants and majority of the findings affirm the pathogenicity of thenonsense and frameshift TMCO1 variantsand their associations with clinical phenotypes. Thus functional properties ofthe single nucleotide variants causing amino acid changes in the TMCO1 are yetto be comprehensively elucidated. In this study, we evaluated the effects ofamino acid substitutions on protein structure, identified their putative rolesin post-translational modifications (PTM) and in regulatory mechanism for TMCO1protein. We classified 41 missense variants as pathogenic based on combinedscores of common in silico tools (SIFT, MutationTaster2, Polyphen2). Of these41 variants, four (p.K211Q, p.K105E, p.S235F, p.K237R) were identified to belocated in PTMs and regulatory protein binding sites; thus they were proposedto be putative functional variants. Moreover, rs1387528611 (p.Lys128Gln) hadalso strong evidence (RegulomeDB score=2b) for its possible regulatoryfunction. The results of our in silico analyses highlight the functionalimportance of the missense TMCO1variants that may contribute to the TMCO1-associateddisease phenotypes and further in vivo evaluation yet to be needed to uncovertheir role in human diseases.
KW  - TMCO1
KW  - Cerebro-facio-thoracic dysplasia
KW  - RegulomeDB
KW  - SNV
KW  - post-translational modifications
KW  - in silico analyses
N2  - Transmembran and Coiled-Coil Domains 1 (TMCO1) proteini, TMCO1 geni tarafından kodlanır ve 7ekzondan oluşur. Önceki çalışmalar serebrofasiotorasik displazili (SFTD)hastalarda çok sayıda TMCO1 varyantıtanımlamış ve TMCO1 lokusunun primeraçık açılı glokom hastalığı ile (PAAG) ilişkili olduğunu göstermiştir. Bununlabirlikte TMCO1 gen sekansıvaryantlarının ilişkilerini bildiren sınırlı sayıda araştırma vardır ve eldeedilen bulguların çoğu anlamsız mutasyonlar ve çerçeve kayması mutasyonlarının TMCO1 varyantlarının patojenliğini veklinik fenotiplerle ilişkilerini belirtmektedir. Bu nedenle, TMCO1'de aminoasitdeğişikliklerine neden olan tek nükleotid varyantlarının fonksiyonelözellikleri henüz tam olarak açıklanamamıştır. Bu çalışmada aminoasitdeğişikliklerinin protein yapısı üzerindeki etkilerini, post-translasyonmodifikasyonlardaki (PTM) ve TMCO1 proteini için düzenleyici mekanizmadakiolası rollerini belirledik. Yaygın olarak kullanılan in silico araçları (SIFT, MutationTaster2, Polyphen2) ileyaptığımız analizin değerlendirmesine göre 41 adet yanlış anlamlı mutasyonbarındıran varyantı patojenik olarak sınıflandırdık. Bu 41 varyanttan dördü(p.K211Q, p.K105E, p.S235F, p.K237R) PTM ve düzenleyici protein bağlamabölgelerinde yer almaktadır, bu nedenle bu varyantların fonksiyon üzerindeetkili olduğunu düşündük. Bununla birlikte, rs1387528611 (s.Lys128Gln)varyantının (RegulomeDB skoru= 2b) düzenleyici varyant olabileceğine dair güçlübiyolojik kanıtlar olduğunu saptadık. In silico analizlerimizin sonuçları, TMCO1 ile ilişkili hastalıkfenotiplerine katkıda bulunabilecek yanlış anlamlı TMCO1 varyantların fonksiyonel önemini ve insan hastalıklarındakirollerini ortaya çıkarmak için in vivo değerlendirmenin işlevsel öneminivurgulamaktadır.
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UR  - https://doi.org/10.29130/dubited.571528
L1  - https://dergipark.org.tr/en/download/article-file/771502
ER  -