Clinically significant findings of high-risk mutations in human SLC29A4 gene associated with diabetes mellitus type 2 in Pakistani population

Abstract

This study conducted an in-depth analysis combining computational and experimental verifications of the deleterious missense mutations associated with the SLC29A4 protein. The functional annotation of the non-synonymous single nucleotide polymorphism (nsSNPs), followed by structure-function analysis, revealed 13 single nucleotide polymorphisms (SNP) as the most damaging. Among these, six mutants P429T/S, L144S, M108V, N86H, and V79E, were predicted as structurally and functionally damaging by protein stability analysis. Also, these variants are located at evolutionary conserved regions, either buried, contributing to the structural damage, or exposed, causing functional changes in the protein. These mutants were further taken for molecular docking studies. When verified via experimental analysis, the SNPs M108V (rs149798710), N86H (rs151039853), and V79E (rs17854505) showed an association with type 2 diabetes mellitus (T2DM). Minor allele frequency for rs149798710 (A > G) was 0.23 in controls, 0.29 in metformin responders, 0.37 in metformin non-responder, for rs151039853 (A > C) was 0.21 in controls, 0.28 in metformin responders, 0.36 in metformin non-responder and for rs17854505 (T > A) was 0.20 in controls, 0.25 in metformin responders, 0.37 in metformin non-responder. Hence, this study concludes that SLC29A4 M108V (rs149798710), N86H (rs151039853), and V79E (rs17854505) polymorphisms were associated with the increased risk of T2DM as well as with the increased risk towards the failure of metformin therapeutic response in T2DM patients of Pakistan.

Communicated by Ramaswamy H. Sarma

Keywords:

• SNP’s
• polymorphism
• PMAT
• SLC29A4
• diabetes mellitus
• amyloids

Acknowledgements

The entire group is grateful to all the members who agreed to be a part of this study. We acknowledge International Islamic University for providing lab facilities. We also acknowledge PIMS hospital for allowing us to collect blood samples from T2DM patients.

Disclosure statement

The authors have declared that they have no competing interests.

Author's contributions

SM participated in the design of the study, carried out the experiments, performed the statistical analysis, and drafted the manuscript. SK and AG provided lab facilities to conduct experiments. MK helped in statistical analysis. AZ helped in haplotype and LD analysis. RN helped in designing blood collection. ZK carried out the computational analysis and also helped to draft the manuscript. All authors read and approved the final manuscript.