TMCO1 Gen Sekans Varyanlatlarının Fonksiyonel Özelliklerinin In Silico Analizlerlerle Değerlendirilmesi

Yıl 2019, , 1931 - 1946, 31.07.2019

Dilek Pirim , Erva Ulusoy Zeynep Kurt , Niyazi Kaya , Elif Uz-yıldırım

https://doi.org/10.29130/dubited.571528

Öz

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.

Anahtar Kelimeler

TMCO1, Serebrofasiyotorasik displazi, RegulomeDB, SNV, Post-translasyonel modifikasyonlar, in silico analiz

Assessing the Functional Properties of the TMCO1 Sequence Variants by Using In Silico Analyses

Öz

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.

Anahtar Kelimeler

TMCO1, Cerebro-facio-thoracic dysplasia, RegulomeDB, SNV, post-translational modifications, in silico analyses

Kaynakça

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