Prediction and Structural Comparison of Deleterious Coding Nonsynonymous Single Nucleotide Polymorphisms (nsSNPs) in Human LEP Gene Associated with Obesity

Bouafi, Hind; Bencheikh, Sara; Krami, A L Mehdi; Morjane, Imane; Charoute, Hicham; Rafiey, Hassan; Saı̈le, Rachid; Benhnini, Fouad; Barakat, Abdelhamid

doi:10.1155/2019/1832084

Cited by 13 publications

(12 citation statements)

References 60 publications

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“…The RMSD and TM-score of the remaining mutations were nearly similar ( Table 5 ). Similar studies have done on many genes and proteins like the human LEP gene [ 58 ] and TAGAP protein [ 59 ].…”

Section: Resultsmentioning

confidence: 66%

The investigation of nonsynonymous SNPs of human SLC6A4 gene associated with depression: An in silico approach

Hasan

Hakim

Shovon

et al. 2021

Heliyon

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Genetic polymorphism of the SLC6A4 gene is associated with several behavioral disorders, including depression. Since studying the total nonsynonymous single nucleotide polymorphisms (nsSNPs) of the SLC6A4 gene at the population level is a difficult task, we aim to utilize in silico approach to detect the most deleterious nsSNPs of the SLC6A4 gene. In our study, 7 computational tools were used in the initial stage, including SIFT, Polyphen-2, PROVEAN, SNAP2, PhD-SNP, PANTHER, and SNPs&GO to find out the most damaging nsSNPs. In the second phase, we performed structural, functional, and stability analysis of SLC6A4 protein by popular computation tools, including I-Mutant 2.0 and MutPred2. Also, the ConSurf server was utilized to find the conserved region of the SLC6A4 protein to determine the relationship between these conserved regions with high-risk nsSNPs. Based on these analyses, 5 high-risk mutations of the SLC6A4 protein were selected. Then, we carried out comparative modeling by using the Robetta server and aligned the mutant protein model with the native protein structure. Later, we performed the post-translational modification and functional domain analysis of the SLC6A4 protein. This study concludes that Arginine → Tryptophan at position 79 and Arginine → Cysteine at position 104 are the two significant mutations in SLC6A4 protein which might play an essential role in causing diseases. Future studies should take these high-risk nsSNPs (rs1221448303, rs200953188) into consideration while exploring diseases related to the SLC6A4 gene. Besides, our research is the first-ever comprehensive in silico investigation of the SLC6A4 gene. Thus, the findings of this study could be beneficial for developing precision medicines against diseases caused by SLC6A4 malfunction. Furthermore, extensive wet-lab research and experiments on various model organisms might be helpful to investigate the precise role of these damaging nsSNPs of the SLC6A4 gene.

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Section: Resultsmentioning

confidence: 66%

The investigation of nonsynonymous SNPs of human SLC6A4 gene associated with depression: An in silico approach

Hasan

Hakim

Shovon

et al. 2021

Heliyon

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“…One of the SNPs in PPARGC1 (rs8192678[A]) has been reported to be associated with higher triacylglycerol levels ( P = 0.005) [ 17 ]. FASN and LEP are important factors in fatty acid synthesis [ 18 , 19 ]. NR4A3 is a regulator of insulin activity in adipocytes [ 14 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

IRLnc: a novel functional noncoding RNA contributes to intramuscular fat deposition

et al. 2021

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Background Intramuscular fat (IMF) is associated with meat quality and insulin resistance in animals. Research on genetic mechanism of IMF decomposition has positive meaning to pork quality and diseases such as obesity and type 2 diabetes treatment. In this study, an IMF trait segregation population was used to perform RNA sequencing and to analyze the joint or independent effects of genes and long intergenic non-coding RNAs (lincRNAs) on IMF. Results A total of 26 genes including six lincRNA genes show significantly different expression between high- and low-IMF pigs. Interesting, one lincRNA gene, named IMF related lincRNA (IRLnc) not only has a 292-bp conserved region in 100 vertebrates but also has conserved up and down stream genes (< 10 kb) in pig and humans. Real-time quantitative polymerase chain reaction (RT-qPCR) validation study indicated that nuclear receptor subfamily 4 group A member 3 (NR4A3) which located at the downstream of IRLnc has similar expression pattern with IRLnc. RNAi-mediated loss of function screens identified that IRLnc silencing could inhibit both of the RNA and protein expression of NR4A3. And the in-situ hybridization co-expression experiment indicates that IRLnc may directly binding to NR4A3. As the NR4A3 could regulate the catecholamine catabolism, which could affect insulin sensitivity, we inferred that IRLnc influence IMF decomposition by regulating the expression of NR4A3. Conclusions In conclusion, a novel functional noncoding variation named IRLnc has been found contribute to IMF by regulating the expression of NR4A3. These findings suggest novel mechanistic approach for treatment of insulin resistance in human beings and meat quality improvement in animal.

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“…One of the SNPs in PPARGC1 (rs8192678[A]) has been reported to be associated with higher triacylglycerol levels (P = 0.005) [10]. FASN and LEP are important factors in fatty acid synthesis [11,12]. NR4A3 is a regulator of insulin activity in adipocytes [13,14].…”

Section: Discussionmentioning

confidence: 99%

IRLnc: A novel functional noncoding RNA contributes to intramuscular fat deposition

Wang

Zhou

Zhang

et al. 2021

Preprint

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BackgroundIntramuscular fat (IMF) is associated with meat quality and insulin resistance in animals. Research on genetic mechanism of IMF decomposition has positive meaning to pork quality and diseases such as obesity and type 2 diabetes treatment. In this study, an IMF trait segregation population was used to perform RNA sequencing and to analyze the joint or independent effects of genes and long intergenic non-coding RNAs (lincRNAs) on IMF.ResultsA total of 26 genes including six lincRNA genes show significantly different expression between high- and low-IMF pigs. Interesting, one lincRNA gene, named IMF related lincRNA (IRLnc) not only has a 292-bp conserved region in 100 vertebrates but also has conserved up and down stream genes (<10 kb) in pig and humans. Real-time quantitative polymerase chain reaction (RT-qPCR) validation study indicated that nuclear receptor subfamily 4 group A member 3 (NR4A3) which located at the downstream of IRLnc has similar expression pattern with IRLnc. RNAi-mediated loss of function screens identified that IRLnc silencing could inhibit both of the RNA and protein expression of NR4A3. And the in-situ hybridization co-expression experiment indicates that IRLnc may directly binding to NR4A3. As the NR4A3 could regulate the catecholamine catabolism, which could affect insulin sensitivity, we inferred that IRLnc influence IMF decomposition by regulating the expression of NR4A3.ConclusionsIn conclusion, a novel functional noncoding variation named IRLnc has been found contribute to IMF by regulating the expression of NR4A3. These findings suggest novel mechanistic approach for treatment of insulin resistance in human beings and meat quality improvement in animal.

show abstract

Prediction and Structural Comparison of Deleterious Coding Nonsynonymous Single Nucleotide Polymorphisms (nsSNPs) in Human LEP Gene Associated with Obesity

Cited by 13 publications

References 60 publications

The investigation of nonsynonymous SNPs of human SLC6A4 gene associated with depression: An in silico approach

The investigation of nonsynonymous SNPs of human SLC6A4 gene associated with depression: An in silico approach

IRLnc: a novel functional noncoding RNA contributes to intramuscular fat deposition

IRLnc: A novel functional noncoding RNA contributes to intramuscular fat deposition

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