Frontonazal Nadir Bir Yüz Malformasyonu ile İlişkili Aday Genlerde Protein Düzeyinde In Silico Analiz

Abstract

Frontonasal malformations are diseases that develop in the median facial line and appear in variable phenotypic features. A family of 5 affected and 2 unaffected individuals were studied by microarray and whole-exome sequencing for a rare frontonasal malformation phenotype prior to the thesis study. In this family, 3 candidate missense mutations (UBXN4; p.E260D, ANK2; p.R1604K, TRAM2; p.E282K) were detected by whole-exome data in candidate gene regions that may be responsible from the disease determined by linkage analysis. In this thesis, it was aimed to investigate the possible structural and functional effects of the 3 candidate mutations on the proteins by in silico methods. For this purpose, primarily sequence-based PredictSNP, MetaSNP, I-Mutant 3.0, Mupro and HOPE tools were used. Afterwards, as the complete experimentally produced 3D structures of proteins could not be obtained from UniProt database, the 3D structures of proteins, encoded by the candidate three genes, were intended to be modelled with different approaches. While the predicted 3D structure of the ANK2 protein could not be formed, the 3D structures of the UBXN4 and TRAM2 proteins were extracted from the AlphaFold database. Structure-based Missense3D, COACH, COFACTOR and PremPS tools were used to survey the effects of mutations that were observed on UBXN4 and TRAM2 proteins on protein structure. In conclusion, 3 candidate variants were predicted to have no possible structural and functional effect on the protein, according to these tools.