Computational Analysis and Polymorphism Study of Tumor Suppressor Candidate Gene-3 for Non Syndromic Autosomal Recessive Mental Retardation

Naveed et al., J Appl Bioinforma Comput Biol 2016, 5:2 DOI: 10.4172/2329-9533.1000127 Journal of Applied Bioinformatics & Computational Biology

Research Article a SciTechnol journal

social, practical adaptive skills and conceptual, originating before 18 Computational Analysis and years [1] and intellectual functioning (I.Q below 70%). It is observed that 1- 3% of general population is affected with MR [2]. Because large Polymorphism study of Tumor numbers of X-linked MR genes are involved in mental retardation which gives ratio between mentally retarded males and females which Suppressor Candidate Gene-3 seem to be quite high at 1.4-:1 to 1.6:1 [3]. Intellectual disability has a very diverse etiology [4]. The causes of ID that affect the development for Non Syndromic Autosomal and functioning of CNS prenatally or postnatally can involve both Recessive Mental Retardation genetic and environmental factors [5]. Muhammad Naveed*, Syeda Khushbakht Kazmi, Fiza Anwar, Prenatal causes of mental retardation include congenital Fatima Arshad, Tehreem Zafar Dar and Muddassar Zafar infections such as cytomegalovirus, toxoplasmosis, syphilis, rubella, herpes and human immunodeficiency virus; prolonged maternal fever in the first trimester; disclosure to alcohol or anticonvulsants; Abstract and untreated maternal phenylketonuria (PKU). Complications of prematurity especially in exceptionally low-birth-weight infants or Mental Retardation (MR) is regarded as a neuronal malfunction certain postnatal exposure can lead to mental retardation/ID [6]. characterized by a low Intellectual Quotient (IQ). To date, few genes (GRIK2, TUSC3, TRAPPC9, TECR, ST3GAL3, MED23, MAN1B1, Genetic causes of MD include genomic disorders, chromosome NSUN1 PRSS12, CRBN, CC2D1A) for autosomal-recessive non structural abnormalities, monogenic diseases and chromosome syndromic MR (NS-ARMR) have been identified and established aneusomies. Such causes account for more than 50% of moderate in various families with MR. The recently reported candidate gene to severe MR, whereas environmental factors (e.g. malnutrition, “Tumor Suppressor Candidate Gene-3 (TUSC3)” was selected for cultural deficit) account for 5-13% and play an essential part in the computational analysis to explore its potential role in pathology pathogenesis of mild ID [7]. as it is the only gene for MR reported in more than five different familial cases worldwide. TUSC3 gene located at chromosome Mental retardation is classified on the basis of transmitted 8p22 contains 11 exons and encodes a protein involved in the genes, either to present on sex chromosome or autosomes. If mental vertebrate plasma membrane magnesium ion transport system. retardation is inherited through autosomes it is called as autosomal Three dimensional structures of the candidate gene TUSC3 MR and if it is related with the X chromosome it is said to be X-linked and its mutated structure with Q55X were generated. Template MR. Phenotypic appearance (dominant or recessive) and mode of parameters were based on Z-score, E value, resolution and quality. inheritance (X-linked and autosomal) are the key determinants of Present study demonstrates the reliability of 3D model which satisfies the overall quality of the model constructed, employing autosomal syndromic and non-syndromic mental retardation. The both physiochemical and statistical model evaluation. Previously identification/recognition of autosomal dominant genes involved in a homozygous 163C-T transition in exon 2 of the TUSC3 gene, MR is quite difficult owing to the low accessibility of large families; resulting in a gln55-to-ter (Q55X) substitution has been reported. suffered individuals rarely reproduce. Up till now, no gene for And here we predicted by PHD-SNP that X could be either proline autosomal dominant non-syndromic MR has been reported other (P) or Aspartic acid (D) causing deleterious effect. As mutation at than several vulnerable genes involved in autosomal dominant MR 55 position was responsible for non-syndromic autosomal recessive have been identified during mapping of chromosomal breakpoints mental retardation, so it was assumed that mutation was either by in patients with balanced chromosomal aberrations [8]. Genotyping proline or aspartic acid. Further, MUPRO, PROVEAN, I-Mutant, Predict SNP, Meta SNP, Panther, SIFT, SNPs 3D confirmed that via microarray analysis has contributed considerably and numerous deleterious mutation was Q55P transition. loci and genes (PRSS12, CRBN, CC2D1A, GRIK2, TRAPPC9, TECR, ST3GAL3, MED23, MAN1B1, and NSUN1) responsible for autosomal Keywords recessive non- syndromic MR (AR-NSMR) have been identified. Mental retardation; Computational analysis; Polymorphism of Tumor suppressor candidate gene 3 is 11 exons gene that encodes TUSC3; Structure prediction; Deleterious mutation; SNP predictor; 348 amino acid protein. I-Mutant The foremost aim of the present study is to perform computational analysis of the gene TUSC3. The three dimensional structure of Introduction TUSC3 has not been identified by NMR and X-ray crystallography. Mental retardation (MR) is a complex phenotype distinguished by We have applied relative modeling to generate the 3D structure suboptimal functioning of the central nervous system (CNS) resulting of TUSC3 The ancestral relationships of TUSC3 were predicted in considerable restrictions in both adaptive behavior as articulated in using homologous genes to construct an ancestral hierarchy of the candidate protein profile. Materials and Methods *Corresponding author: Muhammad Naveed, Department of Biochemistry and Molecular Biology, University of Gujrat, Pakistan 50700, Tel: 00923015524624; The amino acid sequence of TUSC3 was retrieved from the E-mail: [email protected] Universal Protein Resource (UniProt) with accession number Received: July 11, 2016 Accepted: October 15, 2016 Published: October 18, Q13454.1. The sequence was subjected to the 03 position-specific 2016 iteration-Basic local alignment search tool (PSI-BLAST) to

All articles published in Journal of Applied Bioinformatics & Computational Biology are the property of SciTechnol, and is International Publisher of Science, protected by copyright laws. Copyright © 2016, SciTechnol, All Rights Reserved. Technology and Medicine Citation: Naveed M, Kazmi SK, Anwar F, Arshad F, Dar TZ, et al. (2016) Computational Analysis and Polymorphism study of Tumor Suppressor Candidate Gene-3 for Non Syndromic Autosomal Recessive Mental Retardation. J Appl Bioinforma Comput Biol 5:2.

doi: 10.4172/2329-9533.1000127 extort a position- specific scoring matrix (PSSM) from UniRef90 was carried out using ERRAT (Figure 2) and PROSA web servers [9] and then against the protein databank (PDB) [10] with (Figure 3) and PROCHECK (Table 2) for the validation of model 0.5 cutoff. The protein sequence of TUSC3 was subjected to quality and overall quality through VERIFY 3D [16]. RAMPAGE secondary structure analysis using PSI-PRED. I-TESSER was output for Ramachadran plot (Figure 4). used to generate 3D-models for TUSC3 and mutated (Q55X). Phylogenetic analysis Physiochemical information about the predicted wild model and mutated model of TUSC3 was evaluated by PROCHECK [11] and The Molecular Evolutionary Genetic Algorithm (MEGA 5) was statistical analysis was carried out using ERRAT (http://services.mbi. employed on. A distance-based approach was selected to conclude ucla.edu/ERRAT) PROSA web servers and RAMPAGE. And the the ancestral history. The (Neighbor-Joining method) NJ was used to overall quality of proposed model was predicted by VERIFY-3D [12]. build a phylogenetic tree. The interior branch method and bootstrap In order to predict physiochemical properties, ProtParam server was value were implemented to validate the ancestral relationships used; this computes various physical and chemical parameters, i.e., (Figure 5). amino acid composition, atomic composition, estimated half-life, Mutational analysis instability index, molecular weight, theoretical pI, aliphatic index and grand average of hydropathicity (GRAVY) for a particular protein. Software used for mutational analysis of Q55X was explained in Table 3. Phylogenetic analysis PhD-SNP The (Molecular Evolutionary Genetic Algorithm) MEGA 5 [13] was employed on. A distance-based approach was selected to PhD-SNP, [17] a SVM based classifier, classifies substitutions at conclude the ancestral history. The (Neighbor-Joining method) specified position of amino acid in protein sequence and check for NJ was executed to build a phylogenetic tree. The interior branch each possible amino acid replacement and on the base of sequence method and bootstrap value were then implemented for verifying the and profile based prediction, it classifies the mutation as neutral or ancestral relationships. deleterious polymorphism. For TUSC3, PhD-SNP confirmed Q55P and Q55D transitions as disease-related polymorphisms. Mutational analysis MUPRO In literature, it has been reported that Q at 55 position was replaced by X which could be any amino acid. And here we predicted Mupro [18] based on the Support Vector Machines (SVM) and by PHD-SNP that X could be either proline (P) or Aspartic acid (D) neural network calculates the sign of energy change and predicts the causing deleterious effect. As mutation at 55 position was responsible structure stability for mutation. The confidence score between -1 and for non-syndromic autosomal recessive mental retardation, so it 1 is used to measure the confidence of the prediction. was assumed that mutation was either by proline or aspartic acid. A score less than 0 means certain mutation decreases the stability MUPRO, PROVEAN [http://provean.jcvi.org/provean_seq_report. of protein. The smaller the score, the more confident the prediction is. php], I-Mutant, Predict SNP (consensus classifier for prediction of disease-related mutations), Meta SNP, Panther, SIFT, SNPs 3D, Table 1: Physiochemical properties of wild and mutant TUSC3. mutpred confirmed that deleterious mutation was Q55P transition. Properties WILD TUSC3 MUTATED TUSC3 (Q55X) Results C 1798 H 2798 As there is at least one ambiguous Atomic composition Secondary structure prediction N 500 position (X) in the sequence 0 478 considered, the atomic composition PSI-PRED predicts the secondary structure of TUSC3. Conserved S 19 cannot be required. Total no. of amino domains OST3_OST6 and Thioredoxin_like superfamily retrieved 348 348 from NCBI Conserved domains. And before to predicts the tertiary acids structure of TUSC3 , its physiochemical properties was identified Molecular weight 39673.2 39659.4 by ProtParam server; this computes various chemical and physical Theoretical pI 9.93 9.93 parameters, i.e. proteins molecular weight 39673.2, theoretical pI Instability Index 48.76 48.15 9.93, amino acid composition, instability index, molecular weight, Aliphatic Index 87.18 87.18 atomic composition, theoretical pI, estimated half-life, grand average GRAVY -0.087 -0.077 of hydropathicity (GRAVY) for a particular protein and aliphatic index. Results of PROT-PARAM are illustrated in the (Table 1). Tertiary structure prediction Three dimensional models for TUSC3 generated with I-Tesser [14] (Figure 1). A hybrid structure based on threading was generated by using the best aligned parts of all suitable templates. Taking wild structure as template to generate the tertiary structure of mutated (Q55X) and structurally validate both of the structures by PROSA- web, Verify 3d, ERRAT [15] and procheck tools.

3D-Structural validation Figure 1: Proposed 3D structures of TUSC3 and mutated (Q55X) TUSC3 respectively. Validation of Predicted Tertiary structure and Statistical analysis

Volume 5 • Issue 2 • 1000127 • Page 2 of 7 • Citation: Naveed M, Kazmi SK, Anwar F, Arshad F, Dar TZ, et al. (2016) Computational Analysis and Polymorphism study of Tumor Suppressor Candidate Gene-3 for Non Syndromic Autosomal Recessive Mental Retardation. J Appl Bioinforma Comput Biol 5:2.

doi: 10.4172/2329-9533.1000127

Figure 2: ERRAT results(a) Normal TUSC3 87.906 overall quality factor (b) Mutated TUSC3 gives 76.786 overall quality factor.

Figure 3: Screenshots of PROSA-WEB results (a) Z-Score of -0.71 for Normal TUSC3 (b) Z-score -4.33 for mutated TUSC3.

Alternatively, score more than 0 means that the particular mutation Provean increases the stability of protein. The bigger the score, the more confident the prediction is illustrated in Table 4. (Protein Variation Effect Analyzer) v1.1 was developed to predict whether a protein sequence variation affects protein function.

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doi: 10.4172/2329-9533.1000127

Table 2: PROCHECK result of wild TUSC3 and mutated TUSC3. Properties Wild TUSC3 Mutated TUSC3 (Q55X) 68.2% Core 64.6% Core Ramachadran plot : 23.3% Allow 24.9% Allow 5.9% Gener 8.5% Gener 2.6% Disall 2.0% Disall All Ramachadran 66 labeled residues (out of 346) 67 labeled residues (out of 346) Chi1 Chi2 Plots 13 labeled residues (out of 220) 18 labeled residues (out of 219) Max. Deviation: 20.1 Max. Deviation: 22.9 Residue Properties Bad contacts: 6 Bad contacts: 7 Bond length/angle: 13.6 Bond length/angle: 11.2 Dihedrals: -0.88 -0.94 Covalent: -0.41 -0.56 Overall -0.66 -0.74 M/c bond lengths: 99.0% within limits – 1.3% highlighted 98.7% within limits – 1.3% highlighted M/c bong angles: 85.7% within limits – 14.3% highlighted 85.6% within limits – 14.4% highlighted Planar groups: 85.1% within limits – 14.9% highlighted 83.5% within limits – 16.5% highlighted

Figure 4: Rampage analysis (A and B) revealed that the predicted model for TUSC3 had 72.8% residues in favored regions, 18.2% in allowed regions and 9.0% in outlier regions.

The PROVEAN [19] score is equal to or below a predefined 0.180, 0.405 and 0.356 for Q55D transition which indicated as Neutral threshold (e.g. -2.5); the protein variant is found to have deleterious for PANTHER, PhD-SNP, SIFT, SNAP, Meta-SNP respectively. And effect. If the PROVEAN score is above the threshold, the variant is for Q55P, the output score as 0.505, 0.549, 0.040, 0.630 indicated predicted to have a “neutral” effect. For TUSC3, the cutoff for both Disease-related polymorphism for PANTHER, PhD-SNP, SIFT, variant Q55P and Q55D is more than -2.5 so both have deleterious SNAP but for Meta-SNAP the output score was 0.484 consider effect. Software predicts PROVEAN score of -3.701 and -4.899 for as neutral polymorphism. RI values 3 and 0 for Q55D and Q55P Q55D and Q55P respectively. respectively. Meta-SNP I-Mutant Meta-SNP has been optimized to predict if a given single I-Mutant2.0 [20] SVM-based web server for automatic prediction point protein variation can be classified as disease associated of protein stability which changes due to single-site mutations was or polymorphism. It gives brief data by compiling results of trained on a data set derived from ProTherm that is currently the different software which are able to predict mutational changes most inclusive database of experimental data on protein mutations. induced in given sequence of amino acids. The output consists The output predicted the decrease changes in protein stability upon of a table listing the number of the mutated position in sequence the possible mutation for a given position with RI value (Reliability of protein, the new residue and the predictions of the 4 predictors Index) 1 and 2 for Q55D and Q55P transition respectively. The (PATHER, SIFT, PHD-SNP and SNAP), the wild-type residue. DDG value calculated from the unfolding Gibbs free energy value of The mutation is either classified as disease-related polymorphism mutated protein minus unfolding Gibbs free energy value of the wild or neutral. Scores were obtained by predicting via each method. type (Kcal/mol) and it was calculated to be -0.44 kcal/mol for Q55D For TUSC3, Meta-SNP calculated the output score of 0.340, 0.417, polymorphism and -0.40 for Q55P polymorphism and as both DDG

Volume 5 • Issue 2 • 1000127 • Page 4 of 7 • Citation: Naveed M, Kazmi SK, Anwar F, Arshad F, Dar TZ, et al. (2016) Computational Analysis and Polymorphism study of Tumor Suppressor Candidate Gene-3 for Non Syndromic Autosomal Recessive Mental Retardation. J Appl Bioinforma Comput Biol 5:2.

doi: 10.4172/2329-9533.1000127

Figure 5: Phylogenetic tree generated via Neighbor Joining method.

Table 3: Tools with predicted results for the effects of non-synonymous mutation at Q55X (P or D). SOFTWARES Effect of Non-Synonymous Mutation at position 55 in TUSC3 Q55P SCORE Q55D SCORE PHD SNP Disease 3 Disease 2 SVM(-0.36008456) SVM(-0.029251711) Decrease stability of protein Decrease stability of protein Mupro structure Neural network structure Neural network (-0.64596456307584) (-0.862131304611673) PROVEAN Deleterious -4.899 Deleterious -3.701 SVM2 prediction effect (Decrease) SVM2 prediction effect(Decrease) I-Mutant Decrease stability DDG value(-0.40) Decrease stability DDG value(-0.44) RI(2) RI(1) Predict SNP Deleterious 55% Neutral 75% 0.484 0.356 Meta SNP Neutral Neutral RI (O) RI (3) Panther Disease 0.505 Neutral 0.340 SIFT Disease 0.630 Neutral 0.405 SNAP Deleterious 72% Neutral 67% MAPP Deleterious 62% Neutral 63% Polyphen-1 Neutral 67% Neutral 67% Polyphen-2 Neutral 71% Neutral 73% values are below than zero which indicates large decrease of stability Predict SNP because increased stability showed only when DDG value is above than zero. Predict SNP [21] prediction based on other tools as well including MAPP, PhD-SNP, Polyphen-1 & Polyphen-2, SIFT and

Volume 5 • Issue 2 • 1000127 • Page 5 of 7 • Citation: Naveed M, Kazmi SK, Anwar F, Arshad F, Dar TZ, et al. (2016) Computational Analysis and Polymorphism study of Tumor Suppressor Candidate Gene-3 for Non Syndromic Autosomal Recessive Mental Retardation. J Appl Bioinforma Comput Biol 5:2.

doi: 10.4172/2329-9533.1000127

Table 4: Results of Mupro Software for Q55D and Q55P polymorphisms. Mupro Prediction Results Q55D Q55P SVM based prediction Confidence Score -0.029251711 -0.36008456 Effect DECREASE the stability of protein structure DECREASE the stability of protein structure Neural network based prediction Confidence Score -0.862131304611673 -0.645596456307584 Effect DECREASE the stability of protein structure DECREASE the stability of protein structure

SNAP. It predicts the Q55P transition as more deleterious with 55% crystallography gives overall quality factor 87.906 which indicates deleterious effects than Q55D transition with 75% neutral expected good quality results, as it should above 80. PROCHECK ideally, score accuracy rate. MAPP, PhD-SNP, SIFT and SNAP with 62%, 68%, should be above -0.5, below -1.0 may need investigation and for it 53% and 72% deleterious effects respectively while Polyphen-1 and gives the score of -0.66 indicate good quality results and PROSA- Polyphen-2 calculates 67% and 71% neutral expected accuracy for WEB gives z-score of -0.71 which is very close to zero thus indicate Q55P polymorphism. And for Q55D transition, only PhD-SNP the good quality of the model as the expected good result value should consider it deleterious polymorphism with 61% expected accuracy be 0-1. For VERIFY-3D plot results was 76.44% of the residues had and MAPP, Polyphen-1 and Polyphen-2, SIFT and SNAP all other an averaged 3D-1D score >0.2 also indicates good results and for mutation detected tools indicate this transition as neutral with 63%, mutated the VERIFY-3D score is 69.54%. Ramachadran plot (Figure 67%, 73% 53% and 67% neutral expected accuracy rate respectively. 4) and Phylogenetic tree (Figure 5) was also generated to shows the Discussion Phylogenetic relationship with other proteins. In an effort to elucidate one of the gene responsible for non- Previously a homozygous 163C-T transition in exon 2 of the syndromic autosomal recessive mental retardation i.e. [22,23], we TUSC3 gene, resulting in a gln55-to-ter (Q55X) substitution has performed a computational analysis and construct its 3D protein been reported [29]. And here we predicted by PHD-SNP that X could model, a potentially interesting molecular target for the development be either proline (P) or Aspartic acid (D) causing deleterious effect. of drug therapy against NSARMR and also found out the As mutation at 55 positions was responsible for non-syndromic polymorphisms. As in literature, a homozygous truncating mutation autosomal recessive mental retardation, so it was assumed that in the gene (Q55X, 601385.0002) is already identified in 3 Iranian sibs mutation was either by proline or aspartic acid. MUPRO (Table with autosomal recessive severe mental retardation [24]. Our results 4), PROVEAN, I-Mutant, Predict SNP, Meta SNP, Panther, SIFT, demonstrated reliable 3D model prediction by satisfying the overall SNPs 3D (Table 3) confirmed that deleterious mutation was Q55P quality of the model constructed, employing both statistical model transition. PhD-SNP confirmed Q55P and Q55D transitions as and physiochemical evaluation. disease-related polymorphisms. The PROVEAN score is equal to or The gene maps to chromosome 8p22 [25], two transcript variants below a predefined threshold value which is -2.5; the protein variant encoding distinct isoforms [26] have been identified for this gene. thus predicted have a deleterious effect. If the PROVEAN score is Longer isoform (a) with accession number NP_006756 [27] was above the threshold, the variant predicted have a neutral effect. For selected for structural analysis, its structural analysis has not been TUSC3, the cutoff for both variant Q55P and Q55D is more the -2.5 done so we performed secondary structure analysis and our results so both are having deleterious effect. Software predicts PROVEAN shows 348 amino acids containing helices and sheets with two score of -3.701 and -4.899 for Q55D and Q55P respectively. domains thoiredoxin and OST3_OST6 domain retrieved from NCBI Conclusion Conserved domains. Met-01 at the start and Glu-348 as the end residue To accelerate molecular revelation, in silico analysis of the TUSC3 of the sequence. Out of 29 beta sheets, 54 amino acids are involved gene concerned with autosomal recessive non-syndromic mental in helices formation. For three-dimensional structure prediction, retardation (ARNSMR) was carried out by using computational tools. possible templates were identified by repeatedly running three PSI- And the mutations responsible for NS-ARMR are computationally BLAST iterations to extract a position-specific scoring matrix (PSSM) identified and confirmed by using different tools. Previously, in from UniRef90, hits with an E-value below the homology modeling literature transition at 55 position was reported but exactly which cutoff 0.5. The reliability of the predicted model was checked through amino acids replace glutamine was not known. Here, we predicted stereochemical evaluation to determine the deviations from normal either proline or aspartic acid was involved with the replacement bond lengths, dihedrals and non-bonded atom-atom distances also of Q55X. Moreover, it was confirmed Proline transition was more confirmed the quality of the dihedral, covalent and overall bond/angle deleterious polymorphism. distances [28]. The results of overall quality from ERRAT support the reliability and quality of the predicted 3D structure. References 1. Luckasson R, Borthwick-Duffy S, Buntinx J (2000) Mental retardation: The phylogenetic history was constructed with the NJ method. definition, classification, and systems of supports. 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doi: 10.4172/2329-9533.1000127

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Author AffiliationTop Department of Biochemistry and Molecular Biology, University of Gujrat, Pakistan

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