Publications by authors named "Tariq Masoodi"

34 Publications

Occurrence of granulovirus infecting in high altitude cold arid region of India.

Virusdisease 2020 Dec 26;31(4):517-525. Epub 2020 Nov 26.

Division of Forestry, Sher-E-Kashmir University of Agriculture Science and Technology, Kashmir (SKUAST-K), Shalimar, Srinagar, Jammu and Kashmir India.

Codling moth (, Lepidoptera: Tortricidae) is a quarantine pest of apple in Ladakh, India. We report granulovirus from infected larvae of codling moth for the first time in India. The two CpGV isolates were identified as (CpGV SKUAST-1 and CpGV SKUAST-2) and published in Genbank under accession number, MK801791 and MK801792, respectively. The mortality of CpGV was evaluated against 3rd instar larvae of codling moth at various concentrations viz., 10, 10, 10, 10, 10, 10 and 10 OB/ml. The median lethal concentrations (LC and LC) were observed at 7.08 and 28.56 OB/ml, respectively. In field, the infection rate by CpGV was 5.95 to 15.65%. Based on typical infection symptoms on the larvae, morphological features under the microscope and sequence results of the amplified product confirmed the first occurrence of CpGV from India. Thus, CpGV will form an important non-chemical strategy for managing this pest.
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http://dx.doi.org/10.1007/s13337-020-00638-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749020PMC
December 2020

Clonal Evolution and Timing of Metastatic Colorectal Cancer.

Cancers (Basel) 2020 Oct 12;12(10). Epub 2020 Oct 12.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide, where ~50% of patients develop metastasis, despite current improved management. Genomic characterisation of metastatic CRC, and elucidating the effects of therapy on the metastatic process, are essential to help guide precision medicine. Multi-region whole-exome sequencing was performed on 191 sampled tumour regions of patient-matched therapy-naïve and treated CRC primary tumours ( = 92 tumour regions) and metastases ( = 99 tumour regions), in 30 patients. Somatic variants were analysed to define the origin, composition, and timing of seeding in the metastatic progression of therapy-naïve and treated metastatic CRC. High concordance, with few genomic differences, was observed between primary CRC and metastases. Most cases supported a late dissemination model, via either monoclonal or polyclonal seeding. Polyclonal seeding appeared more common in therapy-naïve metastases than in treated metastases. Whereby, treatment prompted for the selection of distinct resistant clones, through monoclonal seeding to distant metastatic sites. Overall, this study reinforces the importance of early clinical detection and surgical excision of the CRC tumour, whilst further highlighting the clinical challenges for metastatic CRC with increased intratumour heterogeneity (either due to early dissemination or polyclonal metastatic spread) and the underlying risk of future therapeutic resistance in treated patients.
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http://dx.doi.org/10.3390/cancers12102938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601934PMC
October 2020

POLE and POLD1 pathogenic variants in the proofreading domain in papillary thyroid cancer.

Endocr Connect 2020 Oct;9(9):923-932

Human Cancer Genomic Research, Research Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Thyroid cancer is the most frequent endocrine cancer with an increasing incidence rate worldwide and is the second most common malignancy among females in Saudi Arabia. Papillary thyroid cancer (PTC) is the most common subtype. Germline pathogenic variants in the proofreading domain of the POLE and POLD1 genes predispose to several types of cancers. However, the role of pathogenic variants of these two genes in PTC remains unknown. Capture sequencing, Sanger sequencing and immunohistochemistry were performed on 300 PTC cases from the Middle Eastern region. One germline pathogenic variant each of POLE (1/300, 0.33%) and POLD1 (1/300, 0.33%) genes was identified. Low expression of POLD1 was detected in 46.5% (133/286) of cases and was significantly associated with the follicular variant of PTC (P = 0.0006), distant metastasis (P = 0.0033) and stage IV tumours (P = 0.0081). However, no somatic pathogenic variant was detected in POLE gene. Furthermore, low expression of POLE was noted in 61.7% (175/284) of cases with no significant clinicopathological associations. Our study shows that pathogenic variant in the POLE and POLD1 proofreading domain is a cause of PTC and low expression of POLD1 is associated with poor prognostic markers in the Middle Eastern population. Further studies from different geographic populations are needed to determine the frequency and spectrum of proofreading domain pathogenic variants in POLE and POLD1 genes and in PTC from different ethnicities.
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http://dx.doi.org/10.1530/EC-20-0258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583138PMC
October 2020

POLE and POLD1 germline exonuclease domain pathogenic variants, a rare event in colorectal cancer from the Middle East.

Mol Genet Genomic Med 2020 08 22;8(8):e1368. Epub 2020 Jun 22.

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, iyadh, Saudi Arabia.

Background: Colorectal cancer (CRC) is a major contributor to morbidity and mortality related to cancer. Only ~5% of all CRCs occur as a result of pathogenic variants in well-defined CRC predisposing genes. The frequency and effect of exonuclease domain pathogenic variants of POLE and POLD1 genes in Middle Eastern CRCs is still unknown.

Methods: Targeted capture sequencing and Sanger sequencing technologies were employed to investigate the germline exonuclease domain pathogenic variants of POLE and POLD1 in Middle Eastern CRCs. Immunohistochemical analysis of POLE and POLD1 was performed to look for associations between protein expression and clinico-pathological characteristics.

Results: Five damaging or possibly damaging variants (0.44%) were detected in 1,135 CRC cases, four in POLE gene (0.35%, 4/1,135) and one (0.1%, 1/1,135) in POLD1 gene. Furthermore, low POLE protein expression was identified in 38.9% (417/1071) cases and a significant association with lymph node involvement (p = .0184) and grade 3 tumors (p = .0139) was observed. Whereas, low POLD1 expression was observed in 51.9% (555/1069) of cases and was significantly associated with adenocarcinoma histology (p = .0164), larger tumor size (T3 and T4 tumors; p = .0012), and stage III tumors (p = .0341).

Conclusion: POLE and POLD1 exonuclease domain pathogenic variants frequency in CRC cases was very low and these exonuclease domain pathogenic variants might be rare causative events of CRC in the Middle East. POLE and POLD1 can be included in multi-gene panels to screen CRC patients.
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http://dx.doi.org/10.1002/mgg3.1368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434734PMC
August 2020

Genetic heterogeneity and evolutionary history of high-grade ovarian carcinoma and matched distant metastases.

Br J Cancer 2020 04 26;122(8):1219-1230. Epub 2020 Feb 26.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh, 11211, Saudi Arabia.

Background: High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian carcinoma, associated with poor clinical outcome and metastatic disease. Although metastatic processes are becoming more understandable, the genomic landscape and metastatic progression in HGSOC has not been elucidated.

Methods: Multi-region whole-exome sequencing was performed on HGSOC primary tumours and their metastases (n = 33 tumour regions) from six patients. The resulting somatic variants were analysed to delineate tumour evolution and metastatic dissemination, and to compare the repertoire of events between primary HGSOC and metastasis.

Results: All cases presented branching evolution patterns in primary HGSOC, with three cases further showing parallel evolution in which different mutations on separate branches of a phylogenetic tree converge on the same gene. Furthermore, linear metastatic progression was observed in 67% of cases with late dissemination, in which the metastatic tumour mostly acquires the same mutational process active in primary tumour, and parallel metastatic progression, with early dissemination in the remaining 33.3% of cases. Metastatic-specific SNVs were further confirmed as late dissemination events. We also found the involvement of metastatic-specific driver events in the Wnt/β-catenin pathway, and identified potential clinically actionable events in individual patients of the metastatic HGSOC cohort.

Conclusions: This study provides deeper insights into clonal evolution and mutational processes that can pave the way to new therapeutic targets.
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http://dx.doi.org/10.1038/s41416-020-0763-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156387PMC
April 2020

Germline and proofreading domain mutations in endometrial carcinoma from Middle Eastern region.

Cancer Cell Int 2019 11;19:334. Epub 2019 Dec 11.

1Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, MBC#98-16, P.O. Box 3354, Riyadh, 11211 Saudi Arabia.

Background: Endometrial carcinoma (EC) accounts for 5.8% of all cancers in Saudi females. Although most ECs are sporadic, 2-5% tend to be familial, being associated with Lynch syndrome and Cowden syndrome. In this study, we attempted to uncover the frequency, spectrum and phenotype of germline mutations in the proofreading domain of and genes in a large cohort of ECs from Middle Eastern region.

Methods: We performed Capture sequencing and Sanger sequencing to screen for proofreading domains of and genes in 432 EC cases, followed by evaluation of protein expression using immunohistochemistry. Variant interpretation was performed using PolyPhen-2, MutationAssessor, SIFT, CADD and Mutation Taster.

Results: In our cohort, four mutations (0.93%) were identified in 432 EC cases, two each in and proofreading domains. Furthermore, low expression of POLE and POLD1 was noted in 41.1% (170/1414) and 59.9% (251/419) of cases, respectively. Both the cases harboring mutation showed high nuclear expression of POLE protein, whereas, of the two mutant cases, one case showed high expression and another case showed low expression of POLD1 protein.

Conclusions: Our study shows that germline mutations in and proofreading region are a rare cause of EC in Middle Eastern population. However, it is still feasible to screen multiple cancer related genes in EC patients from Middle Eastern region using multigene panels including and .
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http://dx.doi.org/10.1186/s12935-019-1058-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907229PMC
December 2019

Evolution and Impact of Subclonal Mutations in Papillary Thyroid Cancer.

Am J Hum Genet 2019 11 24;105(5):959-973. Epub 2019 Oct 24.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia. Electronic address:

Unlike many cancers, the pattern of tumor evolution in papillary thyroid cancer (PTC) and its potential role in relapse have not been elucidated. In this study, multi-region whole-exome sequencing (WES) was performed on early-stage PTC tumors (n = 257 tumor regions) from 79 individuals, including 17 who had developed relapse, to understand the temporal and spatial framework within which subclonal mutations catalyze tumor evolution and its potential clinical relevance. Paired primary-relapse tumor tissues were also available for a subset of individuals. The resulting catalog of variants was analyzed to explore evolutionary histories, define clonal and subclonal events, and assess the relationship between intra-tumor heterogeneity and relapse-free survival. The multi-region WES approach was key in correctly classifying subclonal mutations, 40% of which would have otherwise been erroneously considered clonal. We observed both linear and branching evolution patterns in our PTC cohort. A higher burden of subclonal mutations was significantly associated with increased risk of relapse. We conclude that relapse in PTC, while generally rare, does not follow a predictable evolutionary path and that subclonal mutation burden may serve as a prognostic factor. Larger studies utilizing multi-region sequencing in relapsed PTC case subjects with matching primary tissues are needed to confirm these observations.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849094PMC
November 2019

Whole-Exome Sequencing of Matched Primary and Metastatic Papillary Thyroid Cancer.

Thyroid 2020 01 4;30(1):42-56. Epub 2019 Dec 4.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Distant metastasis is a rare occurrence in thyroid cancer, and it can be associated with poor prognosis. The genomic repertoires of various solid malignancies have previously been reported but remain underexplored in metastatic papillary thyroid cancer (PTC). Furthermore, whether distant metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing on 14 matched distant metastases, primary PTC tumors, and normal tissues. Point mutations, copy number alterations, cancer cell fractions, and mutational signatures were defined using the state-of-the-art bioinformatics methods. All likely deleterious variants were validated by orthogonal methods. Genomic differences were observed between primary and distant metastatic deposits, with a median of 62% (range 21-92%) of somatic mutations detected in metastatic tissues, but absent from the corresponding primary tumor sample. Mutations in known driver genes including , , and were shared and preferentially clonal in both sites. However, likely deleterious variants affecting DNA methylation and transcriptional repression signaling genes including , , and were found to be restricted in the metastatic lesions. Moreover, a mutational signature shift was observed between the mutations that are specific or enriched in the metastatic and primary lesions. Primary PTC and distant metastases differ in their range of somatic alterations. Genomic analysis of distant metastases provides an opportunity to identify potentially clinically informative alterations not detected in primary tumors, which might influence decisions for personalized therapy in PTC patients with distant metastasis.
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http://dx.doi.org/10.1089/thy.2019.0052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983753PMC
January 2020

Molecular modelling and dynamics of CA2 missense mutations causative to carbonic anhydrase 2 deficiency syndrome.

J Biomol Struct Dyn 2020 Sep 8;38(14):4067-4080. Epub 2019 Oct 8.

Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.

Carbonic anhydrase 2 (CA2) enzyme deficiency caused by CA2 gene mutations is an inherited disorder characterized by symptoms like osteopetrosis, renal tubular acidosis, and cerebral calcification. This study has collected the CA2 deficiency causal missense mutations and assessed their pathogenicity using diverse computational programs. The 3D protein models for all missense mutations were built, and analyzed for structural divergence, protein stability, and molecular dynamics properties. We found M-CAP as the most sensitive prediction method to measure the deleterious potential of CA2 missense mutations. Free energy dynamics of tertiary structure models of CA2 mutants with DUET, mCSM, and SDM based consensus methods predicted only 50% of the variants as destabilizing. Superimposition of native and mutant CA2 models revealed the minor structural fluctuations at the amino acid residue level but not at the whole protein structure level. Near native molecular dynamic simulation analysis indicated that CA2 causative missense variants result in residue level fluctuation pattern in the protein structure. This study expands the understanding of genotype-protein phenotype correlations underlying CA2 variant pathogenicity and presents a potential avenue for modifying the CA2 deficiency by targeting biophysical structural features of CA2 protein. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2019.1671899DOI Listing
September 2020

Relationship of forest biomass carbon with biophysical parameters in north Kashmir region of Himalayas.

Environ Monit Assess 2019 Aug 5;191(9):541. Epub 2019 Aug 5.

Division of Natural Resource Management, Faculty of Forestry, Sher-e-Kashmir University of Agricultural Sciences and Technology of Kashmir, Benhama Ganderbal, Jammu and Kashmir, 191201, India.

Biophysical parameters affecting biomass carbon have been emphasized in the Paris Agreement for realizing climatic benefits from mitigation projects. The present study was conducted to assess the relation of biophysical parameters with forest biomass carbon in north Kashmir region of Himalayas. The relation of biomass carbon was assessed with (1) species type or strata including Cedrus deodara, mixed I (Cedrus deodara-Pinus wallichiana), mixed II (Abies pindrow-Picea smithiana) and Pinus wallichiana, (2) altitude (1292-2911 m amsl), (3) crown density, (4) aspect, (5) tree count or density and (6) location. Using a stratified sampling design, a total of 188 quadrats of 0.1 ha were laid across the entire region representing different biophysical parameters. Field observation including diameter at breast height and height were recorded and sample biomass (t ha) was estimated using volumetric equations. The observed relation of aboveground biomass carbon with species revealed a trend of mixed II ˃ Cedrus deodara ˃ mixed I ˃ Pinus wallichiana. A positive but weak correlation (R = 0.02) was found between aboveground biomass carbon and altitude. A reasonably good correlation (R = 0.40) was observed to exist between aboveground biomass carbon and crown density. The highest value of average biomass carbon (72.63 t ha) was recorded for the north-eastern aspect whereas the lowest value (44.60 t ha) was recorded for the eastern aspect. The aboveground biomass carbon and tree count was found positively correlated (+ 0.475, R = 0.48). Forest biomass carbon fluctuates within the same geographical region with a variety of biophysical factors. The growth rate of species, photosynthetic ability under different crown densities and climatic conditions could address the reasons for this variability. Biophysical relations of forest biomass carbon can be viewed as an important input for guidelines and policy matters on climate change.
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http://dx.doi.org/10.1007/s10661-019-7669-8DOI Listing
August 2019

Prognostic significance of DNMT3A alterations in Middle Eastern papillary thyroid carcinoma.

Eur J Cancer 2019 08 4;117:133-144. Epub 2019 Jul 4.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia. Electronic address:

Background: Thyroid cancer is the second most common cancer affecting Saudi women after breast cancer, with papillary thyroid carcinoma (PTC) accounting for 80-90% of thyroid cancers. DNA methyltransferases affect DNA methylation, and it is thought that they play an important role in the malignant transformation of various cancers.

Methods: We sought to evaluate the frequency of DNA methyltransferase 3A (DNMT3A) alterations in a large cohort of >1000 PTC cases using exome sequencing, capture sequencing, immunohistochemistry and methylation-specific polymerase chain reaction. We also performed in vitro analysis to investigate the role of DNMT3A methylation in PTC cell lines.

Results: DNMT3A pathogenic mutations were noted in 1.2% (12/1013) of PTC cases. Reduced/loss of DNMT3A expression was seen in 59.8% (579/968) of PTC cases and was significantly associated with the DNMT3A mutation (p = 0.0120). DNMT3A alterations (mutation and/or loss of expression) were associated with aggressive clinical parameters and a poor outcome. The promoter region of the DNMT3A gene was methylated in 57.1% of PTC cases tested and was significantly associated with reduced DNMT3A protein expression (p = 0.0253). Treatment of the methylated PTC cell line with 5-aza-2'-deoxycytidine resulted in demethylation of the DNMT3A gene, leading to restoration of its expression. Demethylation significantly potentiated the TRAIL-mediated apoptosis in PTC cells. Interestingly, silencing of DNMT3A using siRNA suppressed TRAIL-mediated apoptosis.

Conclusion: These findings suggest that DNMT3A alterations play an important role in PTC pathogenesis and demethylation agents can be used to restore the function of DNMT3A in a subset of patients with PTC.
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http://dx.doi.org/10.1016/j.ejca.2019.05.025DOI Listing
August 2019

Structural prediction, whole exome sequencing and molecular dynamics simulation confirms p.G118D somatic mutation of PIK3CA as functionally important in breast cancer patients.

Comput Biol Chem 2019 Jun 29;80:472-479. Epub 2019 May 29.

Department of Biotechnology, K L University, Guntur, Andhra Pradesh, India; Prof. TNA Innovation Center, Varsha Bioscience and Technology India Private Limited, Telangana, India. Electronic address:

To understand the structural and functional importance of PIK3CA somatic mutations, whole exome sequencing, molecular dynamics simulation techniques in combination with in silico prediction algorithms such as SIFT, PolyPhen, Provean and CADD were employed. Twenty out of eighty missense somatic mutations in PIK3CA gene were found to be pathogenic by all the four algorithms. Most recurrent mutations found were known hotspot PIK3CA mutations with known clinical significance like p.E545 K, p.E545A, p.E545 G and p.C420R. A missense mutation p.G118D was found to be recurrently mutated in 5 cases. Interestingly, this mutation was observed in one of the patients who underwent whole exome sequencing and was completely absent from the controls. To see the effect of this mutation on the structure of PIK3CA protein, molecular dynamics simulation was performed. By molecular dynamics approach, we have shown that p.G118D mutation deviated from the native structure which was supported by the decrease in the number of hydrogen bonds, difference in hydrogen bond distance and angle, difference in root mean square deviation between the native and the mutant structures.
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http://dx.doi.org/10.1016/j.compbiolchem.2019.05.012DOI Listing
June 2019

TGFβ-induced SMAD4-dependent Apoptosis Proceeded by EMT in CRC.

Mol Cancer Ther 2019 07 3;18(7):1312-1322. Epub 2019 May 3.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. In Saudi Arabia, colorectal cancer is more aggressive and presents at younger age, warranting new treatment strategies. Role of TGFβ/Smad4 signaling pathway in initiation and progression of colorectal cancer is well documented. This study examined the role of TGFβ/Smad4 signaling pathway in a large cohort of Saudi patients with colorectal cancer, followed by analysis to dissect the dual role of TGFβ on inducing epithelial-to-mesenchymal transition (EMT) and apoptosis. Our study demonstrated high frequency of alterations with low expression of Smad4 protein identifying a subgroup of aggressive colorectal cancer to be an independent marker for poor prognosis. Functional studies using colorectal cancer cells show that TGFβ induces Smad4-dependent EMT followed by apoptosis. Induction of mesenchymal transcriptional factors, Snail1 and Zeb1, was essential for TGFβ-induced apoptosis. Our results indicate that KLF5 acts as an oncogene in colorectal cancer cells regardless of Smad4 expression and inhibition of KLF5 is requisite for TGFβ-induced apoptosis. Furthermore, TGFβ/Smad4 signal inhibits the transcription of KLF5 that in turn switches Sox4 from tumor promoter to suppressor. A high incidence of alterations were found in the Saudi patients with colorectal cancer. Functional study results indicate that TGFβ induces Smad4-dependent EMT followed by apoptosis in colorectal cancer cells.
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http://dx.doi.org/10.1158/1535-7163.MCT-18-1378DOI Listing
July 2019

Prevalence, spectrum, and founder effect of BRCA1 and BRCA2 mutations in epithelial ovarian cancer from the Middle East.

Hum Mutat 2019 06 18;40(6):729-733. Epub 2019 Mar 18.

Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Germline mutations in breast cancer susceptibility gene 1 and 2 have previously been estimated to contribute to 13-18% of all epithelial ovarian cancer (EOC). To characterize the prevalence and effect of BRCA1 and BRCA2 mutations in Middle Eastern EOC patients, BRCA mutation screening was performed in 407 unselected ovarian cancer patients using targeted capture and/or Sanger sequencing. A total of 19 different pathogenic variants (PVs) were identified in 50 (12.3%) women. Nine PVs were recurrent accounting for 80% of cases with PVs (40/50) in the entire cohort. Founder mutation analysis revealed only two mutations (c.4136_4137delCT and c.1140dupG) sharing the same haplotypes thus representing founder mutations in the Middle Eastern population. Identification of the mutation spectrum, prevalence, and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment, and development of a cost-effective screening strategy.
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http://dx.doi.org/10.1002/humu.23736DOI Listing
June 2019

Expanding the spectrum of germline variants in cancer.

Hum Genet 2017 11 3;136(11-12):1431-1444. Epub 2017 Oct 3.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Our ability to identify germline variants in hereditary cancer cases remains challenged by the incomplete cataloging of relevant genes and lack of consensus on who should be tested. We designed a panel [hereditary oncogenesis predisposition evaluation (HOPE)] that encompasses most of the genes known to be associated with cancer development and tested its yield on more than 1300 samples of cancer patients. Pathogenic or likely pathogenic variants in high and intermediate risk genes were identified in 16, 23.9, 9.7 and 2.7%, respectively, of peripheral blood or normal tissue samples taken from patients with breast, ovarian, colorectal and thyroid cancer. To confirm specificity of these findings, we tested an ethnically matched cohort of 816 individuals and only identified pathogenic or likely pathogenic variants in 1.59% (0.98% in high risk and 0.61% in intermediate risk). Remarkably, pathogenic or likely pathogenic alleles in DNA repair/genomic instability genes (other than BRCA2, ATM and PALB2) accounted for at least 16.8, 11.1, 50 and 45.5% of mutation-positive breast, ovarian, thyroid and colorectal cancer patients, respectively. Family history was noticeably lacking in a substantial fraction of mutation-positive cases (63.7, 81.5, 42.4 and 87.5% in breast, ovarian, colorectal and thyroid, respectively). Our results show high contribution of germline mutations to cancer predisposition that extends beyond "classical" hereditary cancer genes. Family history was lacking in 63.5% mutation-positive cases, shows that hereditary cancer need not appear familial and suggests that relaxed selection of cancer patients for hereditary cancer panels should be considered.
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http://dx.doi.org/10.1007/s00439-017-1845-0DOI Listing
November 2017

Computational Analysis of Breast Cancer GWAS Loci Identifies the Putative Deleterious Effect of STXBP4 and ZNF404 Gene Variants.

J Cell Biochem 2017 12 25;118(12):4296-4307. Epub 2017 May 25.

Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.

The genome-wide association studies (GWAS) have enabled us in identifying different breast cancer (BC) susceptibility loci. However, majority of these are non-coding variants with no annotated biological function. We investigated such 78 noncoding genome wide associated SNPs of BC and further expanded the list to 2,162 variants with strong linkage-disequilibrium (LD, r ≥0.8). Using multiple publically available algorithms such as CADD, GWAVA, and FATHAMM, we classified all these variants into deleterious, damaging, or benign categories. Out of total 2,241 variants, 23 (1.02%) variants were extreme deleterious (rank 1), 70 (3.12%) variants were deleterious (rank 2), and 1,937 (86.43%) variants were benign (rank 3). The results show 14% of lead or associated variants are under strong negative selection (GERP++ RS ≥2), and ∼22% are under balancing selection (Tajima's D score >2) in CEU population of 1KGP-the regions being positively selected (GERP++ RS <0) in mammalian evolution. The expression quantitative trait loci of highest deleteriously ranked genes were tested on relevant adipose and breast tissues, the results of which were extended for protein expression on breast tissues. From the concordance analysis of ranking system of GWAVA, CADD, and FATHMM, eQTL and protein expression, we identified the deleterious SNPs localized in STXBP4 and ZNF404 genes which might play a role in BC development by dysregulating its gene expression. This simple approach will be easier to implement and to prioritize large scale GWAS data for variety of diseases and link to the potentially unrecognized functional roles of genes. J. Cell. Biochem. 118: 4296-4307, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcb.26080DOI Listing
December 2017

Exome sequencing identifies novel NTRK1 mutations in patients with HSAN-IV phenotype.

Am J Med Genet A 2017 Apr;173(4):1009-1016

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Hereditary sensory autonomic neuropathy type IV (HSAN-IV) is a rare autosomal recessive disorder that usually begins in infancy and is characterized by anhidrosis, insensitivity to noxious stimuli leading to self-mutilating behavior, and intellectual disability. HSAN-IV is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene, NTRK1, encoding the high-affinity receptor of nerve growth factor (NGF) which maps to chromosome 1q21-q22. Patients with HSAN-IV lack all NGF-dependent neurons, the primary afferents and sympathetic postganglionic neurons leading to lack of pain sensation and the presence of anhidrosis, respectively. Herein, we report nine patients from nine unrelated families with HSAN-IV due to various mutations in NTRK1, five of which are novel. These are three missense and two nonsense mutations distributed in various domains of NTRK1 involved in binding of NGF. The affected patients had variable intellectual deficits, and some had delayed diagnosis of HSAN-IV. In addition to being the first report of HSAN-IV from the Arabian Peninsula, this report expands the mutational spectrum of patients with NTRK1 mutations and provides further insights for molecular and clinical diagnosis.
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http://dx.doi.org/10.1002/ajmg.a.38120DOI Listing
April 2017

Response to Yehia et al.

Am J Hum Genet 2017 03;100(3):564-565

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia. Electronic address:

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http://dx.doi.org/10.1016/j.ajhg.2017.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339109PMC
March 2017

is recurrently mutated in Middle Eastern colorectal cancer.

Gut 2018 Apr 9;67(4):663-671. Epub 2017 Feb 9.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Objective: Colorectal cancer (CRC) is a common cancer and a leading cause of cancer deaths. Previous studies have identified a number of key steps in the evolution of CRC but our knowledge of driver mutations in CRC remains incomplete. Recognising the potential of studying different human populations to reveal novel insights in disease pathogenesis, we conducted genomic analysis of CRC in Saudi patients.

Design: In the discovery phase of the study, we conducted whole genome sequencing of tumour and corresponding germline DNA in 27 patients with CRC. In addition to known driver mutations, we identified three somatic mutations. In the replication phase, we employed a next-generation sequencing approach to capture and sequence and other candidate genes in a larger sample of 400 patients with CRC and confirmed the enrichment for recurrent mutations.

Results: In order to gain insight into a plausible biological mechanism for the potential role of mutations in CRC, we studied CRC cell lines that differ substantially in the expression level of , and found the latter to be correlated inversely with transforming growth factor (TGF)-β signalling and directly with apoptosis in response to chemotherapeutic agents. Importantly, these correlations were replicated when expression was experimentally manipulated.

Conclusions: Our data expand the recently described role of as a tumour suppressor in other cancers to include CRC, and suggest TGF-β signalling as a potential mediator of this effect.
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http://dx.doi.org/10.1136/gutjnl-2016-313334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868237PMC
April 2018

Genomic Profiling of Thyroid Cancer Reveals a Role for Thyroglobulin in Metastasis.

Am J Hum Genet 2016 06 26;98(6):1170-1180. Epub 2016 May 26.

Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia. Electronic address:

Papillary thyroid carcinoma (PTC) has a wide geographic variation in incidence; it is most common in Saudi Arabia, where it is only second to breast cancer as the most common cancer among females. Genomic profiling of PTC from Saudi Arabia has not been attempted previously. We performed whole-exome sequencing of 101 PTC samples and the corresponding genomic DNA to identify genes with recurrent somatic mutations, then sequenced these genes by using a next-generation gene-panel approach in an additional 785 samples. In addition to BRAF, N-RAS, and H-RAS, which have previously been shown to be recurrently mutated in PTC, our analysis highlights additional genes, including thyroglobulin (TG), which harbored somatic mutations in 3% of the entire cohort. Surprisingly, although TG mutations were not exclusive to mutations in the RAS-MAP kinase pathway, their presence was associated with a significantly worse clinical outcome, which suggests a pathogenic role beyond driving initial oncogenesis. Analysis of metastatic PTC tissue revealed significant enrichment for TG mutations (p < 0.001), including events of apparent clonal expansion. Our results suggest a previously unknown role of TG somatic mutations in the pathogenesis of PTC and its malignant evolution.
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http://dx.doi.org/10.1016/j.ajhg.2016.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908175PMC
June 2016

Evaluation and identification of damaged single nucleotide polymorphisms in COL1A1 gene involved in osteoporosis.

Arch Med Sci 2013 Oct 13;9(5):899-905. Epub 2012 May 13.

Health Care Development for Elderly Research Chair, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia.

Introduction: Single-nucleotide polymorphisms (SNPs) are biomarkers for exploring the genetic basis of many complex human diseases. The prediction of SNPs is promising in modern genetic analysis but it is still a great challenge to identify the functional SNPs in a disease-related gene. The computational approach has overcome this challenge and an increase in the successful rate of genetic association studies and reduced cost of genotyping have been achieved. The objective of this study is to identify deleterious non-synonymous SNPs (nsSNPs) associated with the COL1A1 gene.

Material And Methods: The SNPs were retrieved from the Single Nucleotide Polymorphism Database (dbSNP). Using I-Mutant, protein stability change was calculated. The potentially functional nsSNPs and their effect on proteins were predicted by PolyPhen and SIFT respectively. FASTSNP was used for estimation of risk score.

Results: Our analysis revealed 247 SNPs as non-synonymous, out of which 5 nsSNPs were found to be least stable by I-Mutant 2.0 with a DDG value of > -1.0. Four nsSNPs, namely rs17853657, rs17857117, rs57377812 and rs1059454, showed a highly deleterious tolerance index score of 0.00 with a change in their physicochemical properties by the SIFT server. Seven nsSNPs, namely rs1059454, rs8179178, rs17853657, rs17857117, rs72656340, rs72656344 and rs72656351, were found to be probably damaging with a PSIC score difference between 2.0 and 3.5 by the PolyPhen server. Three nsSNPs, namely rs1059454, rs17853657 and rs17857117, were found to be highly polymorphic with a risk score of 3-4 with a possible effect of non-conservative change and splicing regulation by FASTSNP.

Conclusions: Three nsSNPs, namely rs1059454, rs17853657 and rs17857117, are potential functional polymorphisms that are likely to have a functional impact on the COL1A1 gene.
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http://dx.doi.org/10.5114/aoms.2012.28598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832808PMC
October 2013

Mutation in ADAT3, encoding adenosine deaminase acting on transfer RNA, causes intellectual disability and strabismus.

J Med Genet 2013 Jul 25;50(7):425-30. Epub 2013 Apr 25.

Developmental Genetics Unit, King Faisal Specialist Hospital and Research Center, MBC-03 PO BOX 3354, Riyadh 11211, Saudi Arabia.

Background: Intellectual disability (ID) is one of the most common forms of disability worldwide, displaying a wide range of aetiologies and affecting nearly 2% of the global population.

Objective: To describe a novel autosomal recessive form of ID with strabismus and its underlying aetiology.

Materials And Methods: Autozygosity mapping, linkage analysis and exome sequencing were performed in a large multiplex consanguineous family that segregates ID and strabismus. Exome sequencing was independently performed in three other consanguineous families segregating the same disease. Direct sequencing of the resulting candidate gene was performed in four additional families with the same phenotype.

Results: A single missense mutation was identified in ADAT3 in all studied families on an ancient ancestral haplotype. This gene encodes one of two eukaryotic proteins that are necessary for the deamination of adenosine at position 34 to inosine in t-RNA. Our results show the first human mutation in the t-RNA editing machinery and expand the landscape of pathways involved in the pathogenesis of ID.
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http://dx.doi.org/10.1136/jmedgenet-2012-101378DOI Listing
July 2013

Mutation in MPDZ causes severe congenital hydrocephalus.

J Med Genet 2013 Jan;50(1):54-8

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Background: Congenital hydrocephalus is an important birth defect that is heterogeneous in aetiology and clinical presentation. Although genetics is believed to play an important role in the aetiology of non-syndromic congenital hydrocephalus, the overwhelming majority of cases lack mutations in L1CAM, the only disease gene identified to date. The purpose of this study is to identify a novel genetic cause of congenital hydrocephalus.

Methods: Families with congenital hydrocephalus were phenotyped clinically and, in one family, autoyzogisty mapping and linkage analysis were pursued. Sequencing of the genes within the candidate locus was followed by targeted sequencing of the likely candidate gene in two other families.

Results: We have identified a family in which severe congenital hydrocephalus of the communicating type follows an autosomal recessive mode of inheritance. Linkage analysis and autozygosity mapping narrowed the critical interval to 6.9 Mb on 9p24.1-p22.3 spanning just six genes. Direct sequencing of these genes revealed a truncating mutation in MPDZ, encoding a tight junction protein. Remarkably, we have also identified the same founder mutation in a stillbirth with massive congenital hydrocephalus from another family.

Conclusions: Our data strongly support the candidacy of MPDZ as a novel congenital hydrocephalus disease gene.
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http://dx.doi.org/10.1136/jmedgenet-2012-101294DOI Listing
January 2013

Exploration of deleterious single nucleotide polymorphisms in late-onset Alzheimer disease susceptibility genes.

Gene 2013 Jan 30;512(2):429-37. Epub 2012 Aug 30.

Department of Biotechnology, K L University, Andhra Pradesh, India.

Non-synonymous single nucleotide polymorphisms (nsSNPs) are considered as biomarkers to disease susceptibility. In the present study, nsSNPs in CLU, PICALM and BIN1 genes were screened for their functional impact on concerned proteins and their plausible role in Alzheimer disease (AD) susceptibility. Initially, SNPs were retrieved from dbSNP database, followed by identification of potentially deleterious nsSNPs and prediction of their effect on proteins by PolyPhen and SIFT. Protein stability and the probability of mutation occurrence were predicted using I-Mutant and PANTHER respectively. SNPs3D and FASTSNP were used for the functional analysis of nsSNPs. The functional impact on the 3D structure of proteins was evaluated by SWISSPDB viewer and NOMAD-Ref server. On analysis, 3 nsSNPs with IDs rs12800974 (T158P) of PICALM and rs11554585 (R397C) and rs11554585 (N106D) of BIN1 were predicted to be functionally significant with higher scores of I-Mutant, SIFT, PolyPhen, PANTHER, FASTSNP and SNPs3D. The mutant models of these nsSNPs also showed very high energies and RMSD values compared to their native structures. Current study proposes that the three nsSNPs identified in this study constitute a unique resource of potential genetic factors for AD susceptibility.
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http://dx.doi.org/10.1016/j.gene.2012.08.026DOI Listing
January 2013

Screening and structural evaluation of deleterious Non-Synonymous SNPs of ePHA2 gene involved in susceptibility to cataract formation.

Bioinformation 2012 28;8(12):562-7. Epub 2012 Jun 28.

Age-related cataract is clinically and genetically heterogeneous disorder affecting the ocular lens, and the leading cause of vision loss and blindness worldwide. Here we screened nonsynonymous single nucleotide polymorphisms (nsSNPs) of a novel gene, EPHA2 responsible for age related cataracts. The SNPs were retrieved from dbSNP. Using I-Mutant, protein stability change was calculated. The potentially functional nsSNPs and their effect on protein was predicted by PolyPhen and SIFT respectively. FASTSNP was used for functional analysis and estimation of risk score. The functional impact on the EPHA2 protein was evaluated by using SWISSPDB viewer and NOMAD-Ref server. Our analysis revealed 16 SNPs as nonsynonymous out of which 6 nsSNPs, namely rs11543934, rs2291806, rs1058371, rs1058370, rs79100278 and rs113882203 were found to be least stable by I-Mutant 2.0 with DDG value of > -1.0. nsSNPs, namely rs35903225, rs2291806, rs1058372, rs1058370, rs79100278 and rs113882203 showed a highly deleterious tolerance index score of 0.00 by SIFT server. Four nsSNPs namely rs11543934, rs2291806, rs1058370 and rs113882203 were found to be probably damaging with PSIC score of ≥ 2. 0 by Polyp hen server. Three nsSNPs namely, rs11543934, rs2291806 and rs1058370 were found to be highly polymorphic with a risk score of 3-4 with a possible effect of Non-conservative change and splicing regulation by FASTSNP. The total energy and RMSD value was higher for the mutant-type structure compared to the native type structure. We concluded that the nsSNP namely rs2291806 as the potential functional polymorphic that is likely to have functional impact on the EPHA2 gene.
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http://dx.doi.org/10.6026/97320630008562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398778PMC
August 2012

In silico analysis of Single Nucleotide Polymorphisms (SNPs) in human BRAF gene.

Gene 2012 Oct 21;508(2):188-96. Epub 2012 Jul 21.

Institute of Molecular Sciences and Bioinformatics Lahore, Pakistan.

BRAF gene mutations are frequently seen in both inherited and somatic diseases. However, the harmful mutations for BRAF gene have not been predicted in silico. Owing to the importance of BRAF gene in cell division, differentiation and secretion processes, the functional analysis was carried out to explore the possible association between genetic mutations and phenotypic variations. Genomic analysis of BRAF was initiated with SIFT followed by PolyPhen and SNPs&GO servers to retrieve the 85 deleterious non-synonymous SNPs (nsSNPs) from dbSNP. A total of 5 mutations i.e. c.406T>G (S136A), c.1446G>T (R462I), c.1556 A>G (K499E), c.1860 T>A (V600E) and c.2352 C>T (P764L) that are found to exert benign effects on the BRAF protein structure and function were chosen for further analysis. Protein structural analysis with these amino acid variants was performed by using I-Mutant, FOLD-X, HOPE, NetSurfP, Swiss PDB viewer, Chimera and NOMAD-Ref servers to check their solvent accessibility, molecular dynamics and energy minimization calculations. Our in silico analysis suggested that S136A and P764L variants of BRAF could directly or indirectly destabilize the amino acid interactions and hydrogen bond networks thus explain the functional deviations of protein to some extent. Screening for BRAF, S136A and P764Lvariants may be useful for disease molecular diagnosis and also to design the molecular inhibitors of BRAF pathways.
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http://dx.doi.org/10.1016/j.gene.2012.07.014DOI Listing
October 2012

Functional genomics based prioritization of potential nsSNPs in EPHX1, GSTT1, GSTM1 and GSTP1 genes for breast cancer susceptibility studies.

Genomics 2012 Jun 1;99(6):330-9. Epub 2012 May 1.

Department of Biotechnology, K L University, Andhra Pradesh, India.

In the present study, nsSNPs in EPHX1, GSTT1, GSTM1 and GSTP1 genes were screened for their functional impact on concerned proteins and their plausible role in breast cancer susceptibility. Initially, SNPs were retrieved from dbSNP, followed by identification of potentially deleterious nsSNPs using PolyPhen and SIFT. Functional analysis was done with SNPs3D, SNPs&GO and MutPred methods. Prediction and evaluation of the functional impact on the 3D structure of proteins were performed with Swiss PDB viewer and NOMAD-Ref servers. On analysis, 13 nsSNPs were found to be highly deleterious and damaging to the protein structure, of which 6 nsSNPs, rs45549733, rs45506591 and rs4986949 of GSTP1, rs72549341 and rs148240980 of EPHX1 and rs17856199 of GSTT1 were predicted to be potentially polymorphic. It is therefore hypothesized that the 6 identified nsSNPs may alter the detoxification process and elevate carcinogenic metabolite accumulation thus modifies the risk of breast cancer susceptibility in a group of women.
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http://dx.doi.org/10.1016/j.ygeno.2012.04.006DOI Listing
June 2012

Screening and Evaluation of Deleterious SNPs in APOE Gene of Alzheimer's Disease.

Neurol Res Int 2012 13;2012:480609. Epub 2012 Mar 13.

Health Care Development for Elderly Research Chair, Community Health Sciences Department, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh 11433, Saudi Arabia.

Introduction. Apolipoprotein E (APOE) is an important risk factor for Alzheimer's disease (AD) and is present in 30-50% of patients who develop late-onset AD. Several single-nucleotide polymorphisms (SNPs) are present in APOE gene which act as the biomarkers for exploring the genetic basis of this disease. The objective of this study is to identify deleterious nsSNPs associated with APOE gene. Methods. The SNPs were retrieved from dbSNP. Using I-Mutant, protein stability change was calculated. The potentially functional nonsynonymous (ns) SNPs and their effect on protein was predicted by PolyPhen and SIFT, respectively. FASTSNP was used for functional analysis and estimation of risk score. The functional impact on the APOE protein was evaluated by using Swiss PDB viewer and NOMAD-Ref server. Results. Six nsSNPs were found to be least stable by I-Mutant 2.0 with DDG value of >-1.0. Four nsSNPs showed a highly deleterious tolerance index score of 0.00. Nine nsSNPs were found to be probably damaging with position-specific independent counts (PSICs) score of ≥2.0. Seven nsSNPs were found to be highly polymorphic with a risk score of 3-4. The total energies and root-mean-square deviation (RMSD) values were higher for three mutant-type structures compared to the native modeled structure. Conclusion. We concluded that three nsSNPs, namely, rs11542041, rs11542040, and rs11542034, to be potentially functional polymorphic.
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http://dx.doi.org/10.1155/2012/480609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317072PMC
August 2012

Functional analysis and structure determination of alkaline protease from Aspergillus flavus.

Bioinformation 2012 28;8(4):175-80. Epub 2012 Feb 28.

Proteases are one of the highest value commercial enzymes as they have broad applications in food, pharmaceutical, detergent, and dairy industries and serve as vital tools in determination of structure of proteins and polypeptides. Multiple application of these enzymes stimulated interest to discover them with novel properties and considerable advancement of basic research into these enzymes. A broad understanding of the active site of the enzyme and of the mechanism of its inactivation is essential for delineating its structure-function relationship. Primary structure analysis of alkaline protease showed 42% of its content to be alpha helix making it stable for three dimensional structure modeling. Homology model of alkaline protease has been constructed using the X-ray structure (3F7O) as a template and swiss model as the workspace. The model was validated by ProSA, SAVES, PROCHECK, PROSAII and RMSD. The results showed the final refined model is reliable. It has 53% amino acid sequence identity with the template, 0.24 Å as RMSD and has -7.53 as Z-score, the Ramachandran plot analysis showed that conformations for 83.4 % of amino acid residues are within the most favored regions and only 0.4% in the disallowed regions.
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http://dx.doi.org/10.6026/97320630008175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3301997PMC
August 2012