Background: The Human Leukocyte Antigen G (HLA-G) protein is an immune tolerogenic molecule with 7 isoforms. The change of expression level and some polymorphisms of the HLA-G gene are involved in various pathologies. Therefore, this study aimed to predict the most deleterious missense non-synonymous single nucleotide polymorphisms (nsSNPs) in HLA-G isoforms via in silico analyses and to examine structural and functional effects of the predicted nsSNPs on HLA-G isoforms. Results: Out of 301 reported SNPs in dbSNP, 35 missense SNPs in isoform 1, 35 missense SNPs in isoform 5, 8 missense SNPs in all membrane-bound HLA-G isoforms and 8 missense SNPs in all soluble HLA-G isoforms were predicted as deleterious by all eight servers (SIFT, PROVEAN, PolyPhen-2, I-Mutant 3.0, SNPs&GO, PhD-SNP, SNAP2, and MUpro). The Structural and functional effects of the predicted nsSNPs on HLA-G isoforms were determined by MutPred2 and HOPE servers, respectively. Consurf analyses showed that the majority of the predicted nsSNPs occur in conserved sites. I-TASSER and Chimera were used for modeling of the predicted nsSNPs. rs182801644 and rs771111444 were related to creating functional patterns in 5′UTR. 5 SNPs in 3′UTR of the HLA-G gene were predicted to affect the miRNA target sites. Kaplan-Meier analysis showed the HLA-G deregulation can serve as a prognostic marker for some cancers. Conclusions: The implementation of in silico SNP prioritization methods provides a great framework for the recognition of functional SNPs. The results obtained from the current study would be called laboratory investigations.

One of the major challenges in the analysis of human genetic variation is to distinguish mutations that are functionally neutral from those that contribute to disease. BubR1 is a key protein mediating spindle-checkpoint activation that plays a role in the inhibition of the anaphase-promoting complex/cyclosome (APC/C), delaying the onset of anaphase and ensuring proper chromosome segregation. Owing to the importance of BUB1B gene in mitotic checkpoint a functional analysis using different in silico approaches was undertaken to explore the possible associations between genetic mutations and phenotypic variation. In this work we found that 3 nsSNPs I82N, P334L and R814H have a functional effect on protein function and stability. A literature search revealed that R814H was already implicated in human diseases. Additionally, 2 SNPs in the 5′ UTR region was predicted to exhibit a pattern change in the internal ribosome entry site (IRES), and eight MicroRNA binding sites were found to be highly affected due to 3′ UTR SNPs. These in silico predictions will provide useful information in selecting the target SNPs that are likely to have functional impact on the BUB1B gene.

The GM2-gangliosidoses are autosomal recessive metabolic diseases caused by a reduced ability to metabolize the GM2ganglioside and result in ganglioside accumulation especially in the central nervous system. 1,2 The disorders show a spectrum of clinical severity. Generally, the earlier the age of onset of clinical symptoms is associated with the more severe form of the disease. 3 The GM2-gangliosidoses are caused by mutations in the genes encoding the subunit α (HEXA gene) or subunit β (HEXB gene) of heterodimeric b-hexosaminidase A (HEX A), or its cofactor (the GM2 activator