D76V, L161R, and C117S are the most pathogenic amino acid substitutions with several dangerous consequences on leptin structure, function, and stability

Mohammed Baqur S Al-Shuhaib

doi:10.1186/s43042-019-0033-2

Abstract

BackgroundLeptin is a versatile hormone with a variety of functions, including regulation of food intake by inhibiting hunger. Any deleterious mutation in this protein can lead to serious consequences for the body. This study was conducted to identify the most deleterious non-synonymous single-nucleotide polymorphisms (nsSNPs) of human LEP gene and their impact on its encoded protein.MethodsTo predict the possible impact of nsSNPs on leptin, a total of 90 nsSNPs were retrieved from dbSNP and investigated using many in silico tools which specially designed to analyze nsSNPs’ consequences on the protein structure, function, and stability.ResultsThree nsSNPs, namely D76V, L161R, and C117S, were found to be completely deleterious by all utilized nsSNPs prediction tools, thus affecting leptin protein structure, biological activity, and stability. Evolutionary information indicated L161R and C117S mutations to be located in extremely high conserved positions. Furthermore, several deleterious mechanisms controlled by both L161R and C117S mutations which alter several motifs in the secondary structure of leptin were detected. However, all D76V, L161R, and C117S mutations exhibited alteration in polar interactions in their representative positions. Further in-depth analyses proved several harmful structural effects of the three nsSNPs on leptin, which may lead to multiple intrinsic disorders in the altered protein forms.ConclusionsThis study provides the first comprehensive computation of the effect of the most damaging nsSNPs on leptin. The exploration of these missense mutations may present novel perspectives for various deleterious consequences originated from such amino acids substitutions. The dynamics of leptin performance, therefore, in many biological pathways, may be changed to create a variety of disorders, such as obesity and diabetes. These findings will help in detecting the most harmful variations needed to be screened for clinically diagnosed patients with leptin disorders.Trial registrationISRCTN73824458

Highlights

Leptin is a versatile hormone with a variety of functions, including regulation of food intake by inhibiting hunger
Some in silico analyses have focused on the missense mutations in leptin protein [11], no comprehensive study has published yet to predict the final consequences of the whole amino acid substitutions in this protein
In this study, a series of in silico prediction analyses were utilized to find out most deleterious amino acid substitutions in the coding region of the LEP gene from other substitutions obtained from the dbSNP database by employing multiple computational tools and observing their effect on structure, function, stability, as well as the evolutionary conservation scores with regard to their corresponding amino acid residues in leptin

Summary

Introduction

Leptin is a versatile hormone with a variety of functions, including regulation of food intake by inhibiting hunger. It is well known that mutations can induce several effects on the corresponding proteins either by changing the expression of the affected proteins by substituting the transcription factors [6], interfering with the splicing [7], or by single amino acid substitutions (or nsSNPs) [8] In the latter case, which is present within the coding portion, an alternative amino acid is incorporated in the protein chain and is known to be one of the main causes of the possible alterations in the leptin mode of action, which may lead to several undesired consequences. This study is designed to provide the first in silico-based prediction for the all missense mutations in the human LEP gene to identify the most deleterious SNPs in terms of protein structure, function, and biological interactions

Methods

Results

Conclusion