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. 2024 Mar 31;20(3):261–270. doi: 10.6026/973206300200261

Insights from the SNP analysis of TYMP gene linking MNGIE

Najat Sifeddine 1,2,*, Lamiae Elkhattabi 1,*, Chaimaa Ait El Cadi 1,*, Al Mehdi Krami 1,*, Khadija Mounaji 2,*, Bouchra el khalfi 2,*, Abdelhamid Barakat 1,*
PMCID: PMC11069602  PMID: 38712004

Abstract

TYMP gene, which codes for thymidine phosphorylase (TP) is also known as platelet-derived endothelial cell growth factor (PD-ECGF). TP plays crucial roles in nucleotide metabolism and angiogenesis. Mutations in the TYMP gene can lead to Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) syndrome, a rare genetic disorder. Our main objective was to evaluate the impact of detrimental non-synonymous single nucleotide polymorphisms (nsSNPs) on TP protein structure and predict harmful variants in untranslated regions (UTR). We employed a combination of predictive algorithms to identify nsSNPs with potential deleterious effects, followed by molecular modeling analysis to understand their effects on protein structure and function. Using 13 algorithms, we identified 119 potentially deleterious nsSNPs, with 82 located in highly conserved regions. Of these, 53 nsSNPs were functional and exposed, while 79 nsSNPs reduced TP protein stability. Further analysis of 18 nsSNPs through 3D protein structure analysis revealed alterations in amino acid interactions, indicating their potential impact on protein function. This will help in the development of faster and more efficient genetic tests for detecting TYMP gene mutations.

Keywords: prediction, Mitochondrial Neurogastrointestinal Encephalopathy, Thymidine phosphorylase, nsSNPs, UTR, conservation, stability, molecular Modeling

Background:

The TYMP gene, responsible for producing thymidine phosphorylase (TP), is situated on chromosome 22q13.33 [1]. The TP, also known as platelet-derived endothelial cell growth factor, is an enzyme that plays a crucial role in catalyzing the reversible phosphorolysis of thymidine, deoxyuridine, and their analogs (excluding deoxycytidine). This enzymatic activity leads to the formation of the corresponding bases and 2-deoxy-D-ribose-1-phosphate (2-dR-1-P) [2]. In the human body, the expression of TP, also known as hTP, is noteworthy in several tissues, including macrophage-like cells, the placenta, lymph nodes, spleen, liver, lungs, and peripheral lymphocytes [3]. The TYMP is found to be overexpressed in various cancer types, encompassing head and neck [4], breast [5], lung [6], oral squamous carcinoma [7], esophageal [8], gastric [9], colorectal [10], bladder [11], prostate [12], ovarian [13], and cervical [14] cancers, among several others. Its biological effects in cancer are primarily characterized by strong pro-angiogenic [15] properties and anti-apoptotic activity [16]. Mutations within the TP gene are an uncommon source of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) [17]. Patients diagnosed with MNGIE display a marked reduction in TP activity, accompanied by a pronounced increase in the levels of thymidine and deoxyuridine in both the blood and tissues. This elevated presence of these substances has detrimental effects, causing disruption of mitochondrial DNA [1]. MNGIE presents a clinical profile characterized by a spectrum of symptoms, encompassing ptosis, ophthalmoparesis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, myopathy, leukoencephalopathy, and lactic acidosis. Typically, the onset of MNGIE disease manifests before the age of 30 and sadly leads to the premature mortality of affected individuals between the ages of 20 and 40 [18]. This condition is intricately associated with the depletion and deletion of mitochondrial DNA (mtDNA), resulting from abnormalities in mitochondrial nucleoside/nucleotide metabolism [19]. Nonsynonymous SNPs (nsSNPs) located in coding regions can induce alterations in protein structure and/or function. Furthermore, in untranslated regions (UTRs), they frequently correlate with a range of diseases [20]. Identification of deleterious nsSNPs for most Human genes remains a major challenge in medical genetics. Therefore, it is of interest to identify deleterious SNPs that may affect the TP protein structure and/or function. In silico analyses conducted in this study not only advance our understanding of the impact of deleterious SNPs on TP protein structure and function but also lay a solid foundation for future experimental validations.

Materials and Methods:

Collection of nsSNPs:

Information regarding single nucleotide polymorphisms (SNPs) within the human TP gene was sourced from Ensembl (ensembl.org/), while the FASTA amino acid sequence of the TP protein (P19971) was retrieved from the UniProt database [21].

Prediction of protein alterations:

The pathogenicity of each non-synonymous SNP (nsSNP) collected was predicted using PredictSNP [22], a resource consolidating predictions from various tools including SIFT (Sorting Intolerant from Tolerant) [23] , PolyPhen-2 (Polymorphism Phenotyping v2) [24], PhD-SNP [25], PANTHER [26], and SNAP [27]. SIFT employs sequence homology to predict the impact of coding mutations on protein function, while PolyPhen-2 assesses the influence of substitutions on protein structure and function based on physical properties. PhD-SNP utilizes support vector machine (SVM) methods to classify mutations as disease-causing or benign. PANTHER predicts pathogenicity based on evolutionary patterns. MAPP [24] predictions were based on physicochemical variation in sequence alignments.

Sequence conservation:

ConSurf [28], a web-based algorithm, was employed to predict functionally important regions of the protein by estimating the degree of conservation of amino acid sites based on homology. The given score is between 1 and 9, representing the level of conservation of each amino acid. A score of 9 represents a highly conserved region, a score of 1 represents a highly variable region, and a score of 5 represents the average. This tool also reveals the type of residue in the giving position of the protein, which can be functional or structural and buried or exposed.

Prediction of nsSNPs positions in different protein domains:

The InterPro tool [29] facilitates the prediction of domains and important sites of proteins based on functional analysis and classification into families. In this study, the InterPro tool was utilized to identify the positions of nsSNPs within different protein domains.

System preparation and structural analysis:

The X-ray crystal structure of the human TP protein bound with thymine was retrieved from the Protein Data Bank (PDB) with a resolution of 2.31 Å (PDB ID 2j0f) [30]. Mutant protein structures were generated by substituting amino acids at corresponding positions, followed by energy minimization using the SPDB viewer tool [31] based on the GROMOS 96 force field.

Prediction of the effect of nsSNPs located in the UTR region:

The 5' and 3' untranslated regions (UTRs) play crucial roles in post-transcriptional gene regulation, translation efficiency, mRNA subcellular localization, and stability. UTRScan [32] was employed to predict functional SNPs within these regions. This tool searches submitted sequences for motifs present in UTRsite, which derives data from UTRdb, a curated database updated through primary data mining and experimental validation.

Results:

SNP datasets:

A total of 513 non-synonymous SNPs (nsSNPs) were retrieved from the thymidine phosphorylase (TP) gene data available in Ensembl. Among these, 124 SNPs were identified in the 5' untranslated region (UTR), and 23 were located in the 3' UTR of the human TP gene.

Prediction of deleterious nsSNPs:

Out of 513 nsSNPs, 119 were predicted as deleterious by all integrated tools in PredictSNP and was selected for further analysis (Table 1).Conservation analysis using the Consurf web server revealed that out of 119 nsSNPs analyzed, 82 were located in highly conserved positions. Of these, 53 were identified as functional and exposed residues, while 29 were predicted to be buried. We selected only residues with a high degree of conservation (Figure 1).

Table 1. Software prediction and scores for the 119 deleterious nsSNP of the TYMP gene.

PredictSNP prediction MAPP prediction PhD-SNP prediction PolyPhen-1 prediction PolyPhen-2 prediction SIFT prediction SNAP prediction PANTHER prediction
I40M DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
K43T DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L49R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L49Q DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
Q70H DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
Q70L DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
M74K DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L75R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
M76I DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G82R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
E87D DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
E87Q DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
T92N DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
S98W DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
S98L DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
D114N DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
K115R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
T118R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G119V DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G119R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G120S DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G120R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
V121G DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
V121M DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G122S DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G122D DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
D123G DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
S126R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
A130P DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
P131T DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L133P DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
A134V DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
A134E DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G137S DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
V140M DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
M142V DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
M142T DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
S144R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G145R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
R146S DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
R146H DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L148V DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L148P DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G152R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G153S DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
D156G DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
E159V DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
E159K DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
S160P DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L177P DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G181D DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G186D DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
Q187K DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
S188R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
S188C DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L191P DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
P193S DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
P193L DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
A194T DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
A194V DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
Y199H DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
Y199C DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
R202K DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
R202T DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
D203H DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
D203N DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
T205I DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
V208G DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
V208M DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
S210R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
K222R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G226A DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
K235N DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
A240D DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
V241D DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L251V DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L251P DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L255P DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
V256G DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
V256D DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G263E DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G263R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
A268E DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
A268G DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L270P DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
M273I DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
M273T DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
P276L DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
P276T DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G282S DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G282A DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G282D DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L285P DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
E286G DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
E286K DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
E289A DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
E289K DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
C293R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G296R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L302S DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G310R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L313P DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
A333E DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L334R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
F343C DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
Q350E DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G387D DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
A398P DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L404F DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L404P DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G405R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G407R DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
V419L DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
V419M DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
R408S DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G428S DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G428D DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
G434W DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
L459P DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS DELETERIOUS
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Figure 1.

Figure 1

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Location of different mutations in the human TYMP protein. Mutations that are structurally analyzed are subdivided into four groups: red =deleterious mutations in the glycine- rich loop; green=deleterious mutations in the active site loop; blue = deleterious mutations in the loop involved in stabilization of the dimmer interface; black square = exposed residues; buried residues = red triangle.

Prediction of different domains in TP:

The InterPro tool identified three domains within the TP protein: Glycosyl-Transferase-N-Domain (38-99), Glycosyl-Transferase-Fam3 (110-340), and PYNP-C (388-462). The distribution of highly conserved nsSNPs within these domains is illustrated in Figure 1.

Impact of predicted deleterious mutations on tp stability:

Using I-Mutant 20, DUET, and MUpro web servers, it was found that 79 nsSNPs led to a decrease in the stability of TP. Table 2 summarizes these results.

Table 2. Prediction of change in protein stability using I-Mutant2.0, MUpro and DUET.

SNP ID substitution Mupro DDG I-mutant DUET DDG
rs935752285 I40M decrease -0.94 decrease decrease -0.995
rs752137335 K43T decrease -1.52 decrease decrease -1.645
rs772046185 Q70H decrease -0.98 decrease decrease -0.777
rs1190033207 Q70L increase 0.076 increase increase 0.816
rs1064792859 M76I increase 0.166 decrease decrease -0.233
rs749827433 E87D increase 0.16 decrease decrease -1.726
rs1361630544 E87Q decrease -0.58 decrease decrease -1.11
rs891107196 T92N decrease -0.62 increase decrease -1,37
rs758303113 S98L increase 0,38 increase decrease -0.13
rs758303113 S98W decrease -0.3 increase decrease -1.35
rs1064792861 D114N decrease -1.25 decrease decrease -1.403
rs775841111 K115R decrease -0.87 decrease decrease -1.326
rs767829510 T118R decrease -0.943 decrease decrease -0.779
rs786205559 G119R decrease -1.37 decrease decrease -0.482
rs866018044 G119V decrease -1.36 decrease decrease -0.498
rs863224250 G120R decrease -0.92 decrease decrease -0.539
rs863224250 G120S decrease -0.92 decrease decrease -0.894
rs948237404 V121G decrease -1.65 decrease decrease -2.107
rs1159212438 V121M decrease -0.46 decrease decrease -0.998
rs1388735279 G122D decrease -0.16 decrease decrease -2.386
rs997046759 G122S decrease -0.61 decrease decrease -1.876
rs1452194925 D123G decrease -1.44 decrease decrease -0.682
rs749738967 S126R decrease -0.22 increase decrease -0.53
rs863224255 P131T decrease -0.85 decrease decrease -2.074
rs199901350 A134E decrease -0.352 decrease decrease -3.3385
rs199901350 A134V decrease -0.12 increase decrease -0.512
rs1207543220 V140M decrease -0.41 decrease decrease -1.688
rs751803871 S144R decrease -0.74 decrease decrease -0.763
rs121913037 G145R decrease -0.64 decrease decrease -0.897
rs188802138 R146H decrease -1.25 decrease decrease -1.313
rs1357734207 R146S decrease -1.14 increase decrease -1.239
rs1223312855 L148P decrease -1.75 decrease decrease -1.548
rs1022322270 L148V decrease -1.05 decrease decrease -0.543
rs765604179 G152R decrease 0 decrease decrease -0.058
rs121913038 G153S decrease -1.29 decrease decrease -1.31
rs1064792863 D156G decrease -1.13 decrease decrease -0.777
rs777005301 E159K decrease -0.81 decrease decrease -0.311
rs863224251 E159V decrease -0.02 increase decrease -0.21
rs865961520 P193L decrease -0.06 decrease decrease -0.001
rs1236277429 P193S decrease -0.62 decrease decrease -1.627
rs923009362 A194T decrease -1.568 decrease decrease -1.727
rs1361750261 Y199C increase 0.019 increase decrease -1.29
rs1434418446 Y199H decrease -0.4 decrease decrease -1.089
rs121913041 R202K decrease -1.57 decrease decrease -1.78
rs121913041 R202T decrease -1.54 decrease decrease -2.36
rs765932857 D203H decrease -1.01 decrease decrease -0.656
rs765932857 D203N decrease -0.71 decrease decrease -0.49
rs929350708 T205I decrease -0.5 decrease decrease 0.96
rs1064792867 V208G decrease -4.1 decrease decrease -2.369
rs121913039 V208M decrease -0.7 decrease decrease -0.876
rs149977726 K222R decrease -0.76 decrease decrease -2.03
rs780762083 V231A decrease -3.5 decrease decrease -2.483
rs1372616333 K235N decrease -1.02 increase decrease -1.17
rs568773673 A240D decrease -0.7 decrease decrease -0.703
rs758373793 V241D decrease -0.86 decrease decrease -0.681
rs1487581282 L251P decrease -1.91 decrease decrease -2.028
rs1487581282 L251V decrease -1.07 decrease decrease -1.812
rs1199784789 G263E decrease -0.42 increase decrease -0.302
rs9628204 G263R decrease -0.46 decrease decrease -0.514
rs369432373 A268E decrease -0.61 decrease decrease -2.41
rs369432373 A268G decrease -1.39 decrease decrease -1.638
rs1190901146 M273I decrease -1.18 decrease decrease -0.665
rs1374755652 M273T decrease -2.22 decrease decrease -1.243
rs1253066888 P276L increase 0.18 decrease decrease -0.216
rs1367937948 P276T decrease -0.78 decrease decrease -1.519
rs745699088 G282A decrease -0.3 decrease decrease -0.653
rs745699088 G282D decrease -0.14 decrease decrease -2.067
rs1297424973 G282S decrease -0.42 decrease decrease -1.442
rs121913042 L285P decrease -1.92 decrease decrease -1.848
rs946234163 E289A Increase 0.21 decrease decrease -0,48
rs946234163 E289K decrease -0.86 decrease decrease -1.272
rs765023287 Q350E decrease -1.5 decrease decrease -1.706
rs1189525116 A398P decrease -1.73 increase decrease -0.827
rs995494519 L404F decrease -1.4 decrease decrease -1.495
rs1455473908 L404P decrease -2.27 decrease decrease -1.966
rs1272848697 G405R decrease -0.19 decrease decrease -0.354
rs863224254 G407R decrease -0.6 decrease decrease -0.622
rs898036117 R408S decrease -0.59 decrease decrease -2.137
rs1035967828 V419L decrease -0.18 decrease decrease -0.733
rs1035967828 V419M decrease -0.52 decrease decrease -1.174
rs1275136706 G428D decrease -0.25 decrease decrease -2.857
rs1064792874 G428S decrease -0.76 decrease decrease -2.158
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Structural analysis:

18 deleterious nsSNPs were selected for investigation. These chosen nsSNPs encompassed three variants located within residues crucial for thymine binding (R202K, R202T, and T118R), eight situated proximally to the active site (G120R, G120S, V121G, G122D, G122S, D123G, V208G, and V241D), two positioned within the loop involved in the closed conformation and stabilization of the dimer interface (G407R and R408S), and eight nsSNPs identified within the phosphate-binding site (S144R, G145R, R146H, R146S, and G153S). The substitution of arginine with threonine at position T118 resulted in the formation of a covalent bond with the thymine ligand and alterations in hydrophobic and hydrogen interactions compared to the native TP form. Mutations R202K and R202T led to the loss of hydrogen bonds with the thymine ligand and significant variations in hydrophobic interactions compared to the native form. The replacement of valine with guanine at conserved position 208 disrupted the hydrophobic interaction network compared to native TP. The V241D variant displayed destabilization in the hydrophobic domains, characterized by the acquisition of hydrophobic bonds with thymine and the loss of an interaction with IL241 compared to native TP. Additionally, the eight nsSNPs (S144R, G145R, R146H, R146S, L148P, L148V, G152R, and G153S) located in the phosphate-binding site, a highly conserved region, induced changes in both hydrophobic and hydrogen interactions.

Prediction of deleterious nsSNPs in UTRs:

Using the UTRscan server, 32 SNPs were predicted to be functional in the internal ribosome entry site (IRES) within the 5' UTR of the TP gene. These functional SNPs are listed in Table 3.

Table 3. SNPs (UTR mRNA) that were predicted to be functionally significant by UTRscan.

SNP ID Nucleotide change UTR position Functional element
rs560027665 A/G 5'UTR IRES signal
rs1462773364 G/T 5'UTR IRES signal
rs999716676 G/A 5'UTR IRES signal
rs1433459572 C/T 5'UTR IRES signal
rs1297495211 G/C 5'UTR IRES signal
rs1366475489 C/G 5'UTR IRES signal
rs1235847706 G/A 5'UTR IRES signal
rs1254678473 C/T 5'UTR IRES signal
Ers1344522161 C/A 5'UTR IRES signal
rs902800658 G/A 5'UTR IRES signal
rs1025395522 A/G 5'UTR IRES signal
rs895613086 A/C,G,T 5'UTR IRES signal
rs1056976904 C/T 5'UTR IRES signal
rs1433747756 G/C 5'UTR IRES signal
rs1375747015 G/C,T 5'UTR IRES signal
rs939884415 C/A 5'UTR IRES signal
rs895147632 T/C 5'UTR IRES signal
rs1055185491 C/T 5'UTR IRES signal
rs1048500050 G/A 5'UTR IRES signal
rs1409562773 C/T 5'UTR IRES signal
rs541255050 C/G 5'UTR IRES signal
rs1299593050 C/T 5'UTR IRES signal
rs921271717 T/C 5'UTR IRES signal
rs1040337014 G/A 5'UTR IRES signal
rs577017185 T/A,C 5'UTR IRES signal
rs750561393 T/A 5'UTR IRES signal
rs912835892 C/G 5'UTR IRES signal
rs912835892 C/G 5'UTR IRES signal
rs1323544073 C/T 5'UTR IRES signal
rs1264647720 G/T 5'UTR IRES signal
rs779073537 C/A,T 5'UTR IRES signal
rs571316178 T/C 5'UTR IRES signal
rs370124042 G/C,T 5'UTR IRES signal
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Discussion:

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an uncommon autosomal recessive disorder that arises from mutations in the TP gene, causing dysfunction of the TP enzyme. TP functions as a homodimeric enzyme, with each subunit consisting of an α-helical domain (α domain) and a substantial α/β domain. These two domains are separated by a significant cleft that accommodates the active site for substrate binding [33]. Multiple reported missense mutations in the TP gene have been associated with the development of MNGIE [34]. A non-synonymous single nucleotide polymorphism (nsSNP) refers to a single-base alteration within the coding region of a gene, leading to the substitution of one amino acid for another in the corresponding protein. Investigating nsSNPs with functional relevance to diseases is a crucial goal in the fields of human molecular biology and medical research. Nevertheless, the sheer abundance of identified SNPs poses challenges in elucidating their biological significance through traditional wet laboratory experiments [35]. Over the past few decades, many studies have employed computational methods to assess the influence of mutations on protein structure and function. These approaches are effective in predicting whether a single-nucleotide polymorphism (SNP) has the potential to lead to a disease. In this work, different computational tools were used to identify the impact of nsSNPs on TP structure and stability. The total of 513 nsSNPs was analyzed by PredictSNP, and 119 of them were predicted to be the most deleterious. Additionally, we found 82 nsSNPs in highly conserved positions, including 54 nsSNPs in functional residues and 28 nsSNPs in structural residues.

The examination of the relationship between predicted amino acid alterations and the thermodynamic stability of proteins, as well as their impact on cellular stability and pathogenicity, implies that a decrease in stability may play a crucial role in the onset and progression of inherited diseases. It has been suggested that variants leading to the destabilization of proteins can disrupt their normal cellular functions, potentially giving rise to various genetic disorders [36]. In this study, the stability analysis revealed that the 79 nsSNPs reduced protein stability according to all the prediction tools employed. Only 18 deleterious nsSNPs were selected for molecular analysis based on their localization in the TP domains. This analysis focuses on the comparison of the differences in hydrogen bonds and hydrophobic interactions between the amino acids of the wild-type protein and its mutated forms. The deleterious SNPs (T118R, R202K, and R202T) contribute to thymine binding (Figure 2) and reveal a disruption of thymine binding (Table 3). The T118R mutation does not form a covalent bond with thymine. Instead, this mutation is associated with TP dysfunction, which can lead to the accumulation of thymine and other metabolites. This accumulation, caused by impaired TP enzymatic function, can contribute to the onset of MNGIE disease.

Figure 2.

Figure 2

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Residues contribute to the active site integrity and stability of the closed form. A:R408 (wild type-TYMP), B: S408 (variant type), C: G407 (wild type-TYMP), and D: R407 (variant type). Residues substituted are shown in blue.

Deleterious nsSNPs localized in close proximity to the binding site of TP (G120R, G120S, V121G, G122D, G122S, D123G, V208M, V208G, and V241D) are in highly conserved positions. decrease TP's stability, leading to the disruption of the hydrogen and hydrophobic interaction, which may induce a change in the conformation of TP and may affect protein function. The two highly conserved nsSNPs (G407R and R408S) were localized in the important loop, which could potentially contribute to the integrity and stability of the closed conformation [37]. The structural property comparison between mutant forms and the WT protein showed a large change in the hydrophobic and hydrogen interactions (Figure 2). The residues Arg408, Ser409, and Arg410 make hydrogen bonds between the loop and the rest of the protein. Consequently, the two deleterious mutations are most likely to disrupt the structural and functional features of the WT protein. Eight nsSNPs (S144R, G145R, R146H, R146S, L148P, L148V, G152R, and G153S) are located in the glycine-rich loop, which has an important role in the binding of the catalytic phosphate [38]. Our in silico tests showed that the eight highlighted mutations are in a highly conserved region, decrease the TP's stability, and cause a vast variation in the residue-neighbor interaction compared to the native form (Table 2). We suggest that the studied mutations overall could affect TP catalytic efficiency through two possible mechanisms: decreasing the structural stability of the protein and reducing its binding affinity towards the essential cofactor PI. In addition, phosphate-binding domains of TP are responsible for the initiation of the closed conformation of the active site [39]. We suggested that substitution of glycine with either arginine or serine may cause MNGIE disease occurrence by disrupting phosphate binding or rendering the TP catalysis less effective. Multiple experimental studies involving the TYMP gene have demonstrated that some of the 19 non-synonymous single nucleotide polymorphisms (nsSNPs) are associated with significant manifestations in subjects of diverse ages and phenotypes. For instance, the R202T mutation was discovered in the TP gene of a 55-year-old Dutch woman who presented with ophthalmoplegia, severe bilateral ptosis, muscle atrophy (while maintaining normal muscle strength), intact sensory testing, and hypoactive or absent tendon reflexes. Additionally, she exhibited extensive leukoencephalopathy and polyphasic potentials in her leg muscles [40]. Similarly, the V208M mutation has been described in a 61-year-old Anglo-American woman who presented with a complex array of health issues, including pancreatitis, small intestine ileus, recurrent nausea with vomiting, early satiety, borborygmi, colonic diverticulosis, and hepatopathy. Furthermore, she experiences demyelinating sensorimotor polyneuropathy and has developed ptosis, progressive external ophthalmoplegia (PEO), optic atrophy, hearing loss, patchy leukoencephalopathy, short-term memory disturbances, occasional inappropriate behaviors, insulin-dependent diabetes mellitus, and renal cell carcinoma identified in patients who met the clinical criteria for mitochondrial neurogastrointestinal encephalomyopathy [39]. Moreover, the G145R mutation has been identified in patients presenting clinical symptoms consistent with mitochondrial neurogastrointestinal encephalomyopathy, originating from different regions, including Israel and Puerto Rico. Similarly, the G153S mutation has been identified in affected patients with clinical symptoms consistent with mitochondrial disorders [19]. All of the experimental data strongly align with the findings from our bioinformatic study, thus providing comprehensive evidence for and an explanation of the impact of deleterious nsSNPs on the TYMP gene. The IRES signal was described as a distinct RNA region that directly promotes the binding of 40S ribosomal subunits to mRNA without previous scanning [40]. The impairment of IRES sequences can deregulate mRNA translation and lead to various diseases or disease susceptibilities. Such as Charcot-Marie-Tooth disease (CMTX) [41], multiple myeloma [42], and Fragile X syndrome (FXS) [43]. We defined 32 SNPs in the IRES region; these SNPs may impair TP synthesis and lead to disease. The early detection of these potentially deleterious mutations in the TP gene could enable preventive intervention for individuals at risk, thereby paving the way for a reduction in the prevalence of MNGIE.

Conclusion:

We identified 119 deleterious nsSNPs within the coding region of the TP gene. Out of them, 79 nsSNPs were predicted to perturb protein stability. Moreover, the structural analysis of 18 SNPs revealed disruption of the network of interaction compared to the native form of TP, which could destabilize the TP-Thymine complex and consequently induce the occurrence of the MNGIE disease. Additionally, we identified 32 functional SNPs in the 5' UTR, which could affect protein synthesis and may lead to diseases. This study lays the groundwork for future research aimed at experimentally validating the predictions of our in silico analysis, thereby paving the way for a better understanding of the underlying mechanisms of MNGIE.

Data availability

All the datasets and structures generated for this study are available from the authors.

Table 4. Effect of nsSNPs of TYMP gene on Hydrogenic and hydrphobic interactions.

dbSNPID SNP Hydrogen bonds Hydrophobic bonds
Wild type variant Wilde type variant
rs767829510 T118R Asp233 Val208 and Asp 233 Ile218, Leu251, Val234, Phe242, Gly119, Val241, Ser117, Asp233 and Thymine Leu251, Ileu214, Val 241, Asp 209, Phe242 and thymine
rs121913041 R202K Leu198, Thr205, Thr207, Val208 and thymine Thr205 and Leu198 Ala 200, Val 204, Ile 214, Thyr199, Leu75, Leu213 and Ser217 Ala 200, Val204, Thr207, Val208, Leu75, Thyr199 and Ser217
rs121913041 R202T Leu198, Thr205, Thr207, Val208 and thymine Thr205 and Leu198 Ala 200, Val 204, Ile 214, Thyr199 Leu75, Leu213 and Ser217 Val204, Ala200, Tyr199 Leu75, Thr207, Leu148 Val208
rs1064792867 V208G Arg202 and Ser210 Arg202 and Ser210 Ala206, Asp203, Leu148 and Ile214 Ile214, Ala206
rs758373793 V241D - Thr118, Ile214 and Pro243 -------------------- Thr118, Pro243 and Thymine
rs751803871 S144R Val185 Thr154 and Val185 Met142, Gln187, Lys221, Thr154 and Ile184 Gln187, Lys221, Met142, Ile184, His116 and Ser126
rs121913037 G145R Thymine, Tyr199 and Leu155 Thymine, Tyr199 and Leu155 Leu148, Gly153, His116, Thr118 and Gly119 Leu148, Gly153, His116 Thr118 and Gly119
rs188802138 R146H Tyr199, Glu159 and Asp156 Tyr199 and Asp156 Gly153 and Val166 Gly153 and Leu155
rs188802138 R146S Tyr199, Glu159 and Asp156 Tyr199 Val166 and Gly153 Gly153 and Asp156
rs121913038 G153S Asp156 and Lys157 Tyr199, Asp156 and Lys157 Gly147, Arg146, Leu155 and Gly145 Gly147, Gly146, Gly145 and Leu155
rs948237404 V121G Leu277 Leu277 Asp123, Val281, Ala398 and Pro276 Asp123 and Pro276
rs863224250 G120S Asp123 Asp123 Thr151, Lys235 and Gly122 Thr151, Lys235 and Gly122
rs863224250 G120R Asp123 Asp123, Lys275 and Met237 Thr151, Lys235 and Gly122 Thr151, Lys235 and Gly122
rs997046759 G122S Lys124 Lys124 and Cys280 Gly120, Leu277, Glu286 and Cys280 Gly120, Leu277, Pro276 Glu286 and Val281
rs1388735279 G122D Lys124 Lys124 Gly120, Leu277, Glu286 and Cys280 Gly120, Cys280, Pro276, Gly278 Val281, Arg279, Leu277 and Glu286
rs1452194925 D123G Gly120, Lys157, Val125 Lys235 and Ser117 Gly120 and Lys157 Leu277, Val121 and Glu286 Val121 and Val125
rs898036117 R408S Glu413 and Asp156 ------ His402, Val204, Asp203, Leu415 and Arg410 Asp203, Glu413, His402, Val204 and Arg410
rs863224254 G407R His402 His150 and Ala406 Gly405 and Leu415 Leu415, Gly405, His402, Gly149, Gly152, Thr151 and His283
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Acknowledgments

The authors are thankful to the laboratory of genomics and human genetics at the Pasteur Institute of Morocco for providing encouragement and facilities.

The authors declare that they have no conflicts of interest.

Edited by Peter N Pushparaj

Citation: Sifeddine et al. Bioinformation 20(3):261-270(2024)

Declaration on Publication Ethics: The author's state that they adhere with COPE guidelines on publishing ethics as described elsewhere at https://publicationethics.org/. The authors also undertake that they are not associated with any other third party (governmental or non-governmental agencies) linking with any form of unethical issues connecting to this publication. The authors also declare that they are not withholding any information that is misleading to the publisher in regard to this article.

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References

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Data Availability Statement

All the datasets and structures generated for this study are available from the authors.

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