A novel missense mutation in the FGB gene (p.Gly302Arg) leading to afibrinogenemia

2016 ◽  
Vol 36 (S 02) ◽  
pp. S34-S37 ◽  
Author(s):  
H. Rühl ◽  
G. Detarsio ◽  
A. Biswas ◽  
S. Gupta ◽  
M. Davoli ◽  
...  
Keyword(s):  
Missense Mutation ◽  
In Silico ◽  
In Silico Analysis ◽  
Missense Mutations ◽  
The Novel ◽  
Beta Chain ◽  
The Core ◽  
And Function ◽  
Flanking Regions ◽  
Positively Charged

SummaryAfibrinogenemia represents the rarest form of fibrinogen deficiency. Causative missense mutations occur rarely and may improve the understanding of fibrinogen structure and function. Patients and methods: The propositus was a 26-year-old Argentinian with afibrinogenemia. FGA, FGB and FGG exons and flanking regions were screened by sequencing and the mutant protein was analyzed in silico. Results: A novel missense mutation in the FGB gene (Bbeta Gly272Arg, p.Gly302Arg) was identified. In silico analysis revealed its location in a highly conserved region, which preserves the core fold of the C-terminal beta-chain and is important for proper secretion. A substitution by a positively charged large Arg residue in this area would most likely disturb the core fold by additional interactions with adjacent residues (p.Asp291, p.Asp297, p.Asp311), or by forming of non-native interactions with other proteins, thereby hindering the action of molecular chaperones. Both alternatives would disturb the regular secretion of the beta-chain. Conclusions: The novel mis-sense mutation in the FGB gene causes afibrinogenemia most probably by affecting the secretion of the fibrinogen beta-chain.

scholarly journals In silico analysis of missense mutations in exons 1–5 of the F9 gene that cause hemophilia B

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Lennon Meléndez-Aranda ◽  
Ana Rebeca Jaloma-Cruz ◽  
Nina Pastor ◽  
Marina María de Jesús Romero-Prado
Keyword(s):  
In Silico ◽  
In Silico Analysis ◽  
Hemophilia B ◽  
Missense Mutations ◽  
Silico Analysis

scholarly journals In silico analysis of CDC73 gene revealing 11 novel SNPs associated with Jaw Tumor Syndrome

2019 ◽  
Author(s):  
Abdelrahman H. Abdelmoneim ◽  
Alaa I. Mohammed ◽  
Esraa O. Gadim ◽  
Mayada A.Mohammed ◽  
Sara H. Hamza ◽  
...  
Keyword(s):  
In Silico ◽  
Autosomal Dominant ◽  
In Silico Analysis ◽  
Autosomal Dominant Disorder ◽  
Variable Expression ◽  
Back Ground ◽  
And Function ◽  
Molecular Aberrations ◽  
The Impact ◽  
Silico Analysis

AbstractBack groundhyperparathyroidism-jaw tumor (HPT-JT) is an autosomal dominant disorder with variable expression, with an estimated prevalence of 6.7 per 1,000 population. Genetic testing for predisposing CDC73 (HRPT2) mutations has been an important clinical advance, aimed at early detection and/or treatment to prevent advanced disease. The aim of this study is to assess the effect of SNPs on CDC73 structure and function using different bioinformatics tools.MethodComputational analysis using eight different in-silico tools including SIFT, PROVEAN, PolyPhen-2, SNAP2, PhD-SNP, SNPs&GO, PMut and Imutant were used to identify the impact on the structure and/or function of CDC73 gene that might be causing jaw tumour.ResultsFrom (733) SNPs identified in the CDC73 gene we found that only Eleven were deleterious to the function and structure of protein and expected to cause syndrome.ConclusionEleven substantial genetic/molecular aberrations in CDC73 gene were identified that could serve as actionable targets for chemotherapeutic intervention in patients whose disease is no longer surgically curable.

scholarly journals Comprehensive in silico Analysis of IKBKAP gene that could potentially cause Familial dysautonomia

2018 ◽  
Author(s):  
Mujahed I. Mustafa ◽  
Enas A. Osman ◽  
Abdelrahman H. Abdelmoneiom ◽  
Dania M. Hassn ◽  
Hadeel M. Yousif ◽  
...  
Keyword(s):  
In Silico ◽  
Genetic Disorder ◽  
In Silico Analysis ◽  
Familial Dysautonomia ◽  
Structural Effect ◽  
Structure And Function ◽  
Genetic Studies ◽  
And Function ◽  
Silico Analysis

AbstractBackgroundFamilial dysautonomia (FD) is a rare neurodevelopmental genetic disorder within the larger classification of hereditary sensory and autonomic neuropathies. We aimed to identify the pathogenic SNPs in IKBKAP gene by computational analysis software’s, and to determine the structure, function and regulation of their respective proteins.Materials and MethodsWe carried out in silico analysis of structural effect of each SNP using different bioinformatics tools to predict SNPs influence on protein structure and function.Result41 novel mutations out of 973 nsSNPs that are found be deleterious effect on the IKBKAP structure and function.ConclusionThis is the first in silico analysis in IKBKAP gene to prioritize SNPs for further genetic studies.

scholarly journals Post-lingual non-syndromic hearing loss phenotype: a novel homozygous missense mutation in MITF

2019 ◽  
Author(s):  
Athar Khalil ◽  
Samer Bou Karroum ◽  
Rana Barake ◽  
Gabriel Dunya ◽  
Samer Abou-Rizk ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Exome Sequencing ◽  
Missense Mutation ◽  
The Novel ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Whole Exome ◽  
Genetic Hearing Loss ◽  
Syndromic Hearing Loss ◽  
And Function

Abstract Background Hearing loss (HL) represents the most common congenital sensory impairment with an incidence of 1-5 per 1000 live births. Non-syndromic hearing loss (NSHL) is an isolated finding that is not part of any other disorder accounting for 70% of all genetic hearing loss cases. Methods In the current study, we report a multifactorial genetic mode of inheritance in a NSHL consanguineous family using exome sequencing technology. We evaluated the possible effects of the single nucleotide variants (SNVs) detected in our patients using in silico methods. Results Two bi-allelic SNVs were detected in the affected patients; a MYO15A (. p.V485A) variant, and a novel MITF (p.P338L) variant. Along with these homozygous mutations, we detected two heterozygous variants in well described hearing loss genes (MYO7A and MYH14). The novel p. Pro338Leu missense mutation on the MITF protein was predicted to change the protein structure and function. Conclusion The novel MITF variant is the first bi-allelic SNV in this gene to be associated with an autosomal recessive non-syndromic HL case with a post-lingual onset. Our findings highlight the importance of whole exome sequencing for a comprehensive assessment of the genetic heterogeneity of HL.

scholarly journals In-silico analysis of BCL2 gene using multiple bioinformatics tools to identify the most lethal mutations that are crucial for its structural and functional integrity

2021 ◽  
Author(s):  
Usman Ghani ◽  
Yasir Ali ◽  
Karim Gul ◽  
Aamir sohail ◽  
Rahmat Ullah ◽  
...  
Keyword(s):  
Animal Models ◽  
In Silico ◽  
Tumor Development ◽  
In Silico Analysis ◽  
Vital Role ◽  
Gene Interactions ◽  
Bioinformatics Tools ◽  
Apoptotic Activity ◽  
And Function ◽  
Related Proteins

Abstract BCL2 was the first ever known gene for anti-apoptotic activity, that encodes for essential proteins of the external mitochondrial membrane. Regarding tumorigenesis, deregulated BCL2 expression and related proteins have been recognized as characteristic of several human cancers and there is concrete evidence that the deregulated expression of BCL2 like proteins plays a vital role in tumor development, persistence and therapeutic resistance. Therefore, it is important to identify the polymorphisms of BCL2 that are both structurally and functionally important for research to find their possible malfunctions and therapeutics. For this reason, in our research, we have used a variety of bioinformatics tools to recognize the most destructive nsSNPs that may be important for the structure and function of BCL2. In silico tools, PROVEAN, SIFT, SNP&GO, PhD SNP, and PolyPhen2 included a variety of other tools such as I Mutant, MutPred, and ConSurf, to study their conservation profiles to validate their stability, structural, and functional impacts. Post-transcriptional alteration sites were also predicted followed by application of 3-D mapping with I-TASSER and Phyre2 tools. Furthermore, the gene interactions were mapped via STRING and GeneMANIA. We also found that nsSNPs Q118R (rs759928495), G193R (rs1197820694), R129C (rs777784952), and Ll81V (rs752310933) are the most destructive nsSNPs in BCL2 genes that can have a vital part in BCL2 protein defects and possibly cause different cancers. Gene-gene interactions showed relation of BCL2 with other genes depicting its importance in several pathways and co-expressions. This research is the first of its kind and offers future prospects for the development of dedicated medicines as well. In the animal models, the effects of BCL2 can also be tested in diseases. Such should be the study of BCL2 proteins from cancer patients. The effects of BCL2 can also be tested on animal models.

scholarly journals A Comprehensive In Silico Analysis of the Functional and Structural Impact of Nonsynonymous SNPs in the ABCA1 Transporter Gene

Cholesterol ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-19 ◽  
Author(s):  
Francisco R. Marín-Martín ◽  
Cristina Soler-Rivas ◽  
Roberto Martín-Hernández ◽  
Arantxa Rodriguez-Casado
Keyword(s):  
In Silico ◽  
Rare Variants ◽  
Experimental Studies ◽  
In Silico Analysis ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Experimental Approaches ◽  
And Function

Disease phenotypes and defects in function can be traced to nonsynonymous single nucleotide polymorphisms (nsSNPs), which are important indicators of action sites and effective potential therapeutic approaches. Identification of deleterious nsSNPs is crucial to characterize the genetic basis of diseases, assess individual susceptibility to disease, determinate molecular and therapeutic targets, and predict clinical phenotypes. In this study using PolyPhen2 and MutPred in silico algorithms, we analyzed the genetic variations that can alter the expression and function of the ABCA1 gene that causes the allelic disorders familial hypoalphalipoproteinemia and Tangier disease. Predictions were validated with published results from in vitro, in vivo, and human studies. Out of a total of 233 nsSNPs, 80 (34.33%) were found deleterious by both methods. Among these 80 deleterious nsSNPs found, 29 (12.44%) rare variants resulted highly deleterious with a probability >0.8. We have observed that mostly variants with verified functional effect in experimental studies are correctly predicted as damage variants by MutPred and PolyPhen2 tools. Still, the controversial results of experimental approaches correspond to nsSNPs predicted as neutral by both methods, or contradictory predictions are obtained for them. A total of seventeen nsSNPs were predicted as deleterious by PolyPhen2, which resulted neutral by MutPred. Otherwise, forty two nsSNPs were predicted as deleterious by MutPred, which resulted neutral by PolyPhen2.

Hyperphenylalaninemia in the Czech Republic: Genotype–phenotype correlations and in silico analysis of novel missense mutations

2013 ◽  
Vol 419 ◽  
pp. 1-10 ◽  
Author(s):  
Kamila Réblová ◽  
Zuzana Hrubá ◽  
Dagmar Procházková ◽  
Renata Pazdírková ◽  
Slávka Pouchlá ◽  
...  
Keyword(s):  
Czech Republic ◽  
In Silico ◽  
In Silico Analysis ◽  
Missense Mutations ◽  
The Czech Republic ◽  
Silico Analysis

scholarly journals A Genotype-Phenotype Correlation of Haemophilia a in Victorian Patients with a Description of Novel Mutations

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2498-2498
Author(s):  
Shreerang Sirdesai ◽  
Kerryn Weekes ◽  
Asif Alam ◽  
Huyen A Tran ◽  
Christopher Barnes ◽  
...  
Keyword(s):  
In Silico ◽  
Family Members ◽  
In Silico Analysis ◽  
Clinical Severity ◽  
Missense Mutations ◽  
Phenotype Correlation ◽  
Novel Mutations ◽  
Mild Phenotype ◽  
Genotype Phenotype Correlation ◽  
Silico Analysis

Abstract Aim: Hemophilia A (HA) is caused by abnormalities in the Factor VIII gene. Certain abnormalities correlate with disease severity. Here, we report the genotype-phenotype correlation for all Victorian HA patients. Methods: Using the Australian Bleeding Disorders Registry, Victorian HA patients were identified. All genetic testing was conducted at Southern Health. The testing algorithm is summarized in Figure 1. Mutations were compared with the list of known Factor 8 mutations on the Champ and EAHAD F8 Variant Databases. A PubMed search was undertaken for any mutations not on either database. If this too was unrevealing, the mutation was designated novel. In-silico analysis was conducted on all novel mutations using three open-access, online prediction tools: a) Mutation Taster; b) Poly-Phen 2; c) Human Splice Site Predictor. Results: 318 patients with matched clinical and genetic records were identified. 275 had known FVIII mutations and 36 novel FVIII mutations were discovered. Eight patients (3%) had no mutations identified. (Table 1) In severe HA the intron-22 inversion was the most common mutation (47/122, 38%). Missense mutations predominated in mild and moderate HA. Inhibitors were present in 44/318 patients, the majority of whom had 26/44 (59%) severe HA. 20/36 novel mutations (55%) were associated with severe HA, 12/36 (33%) with mild HA and 4/36 (11%) with a moderate HA. Novel mutations associated with non-severe phenotypes were mostly missense mutations (15/16); More diversity was seen in the novel mutations causing a severe HA with a fairly even distribution of mutations: missense (7/20), nonsense (4/20) and small deletions and insertions (8/20). One large deletion involving a 6.5kb region of exon 26, as well as one duplication of exons 7 to 9 - was seen in the severe group. In-silico analysis predicted that all novel severe HA mutations were likely to be pathogenic.Inhibitors were seen in 7 patients with novel mutations. Of the 36 novel mutations we described, 9/36 (25%) were seen in other family members - often female carriers. All 9 mutations caused a severe phenotype which is not unexpected given that the screening and testing of family members would be unlikely to take place in patients who have a mild phenotype and rarely require supportive medical care Conclusion: This study adds 36 novel mutations to the currently known FVIII haemophilic mutations. It also confirms that the frequency and correlative clinical severity of known genetic mutations in the Victorian HA cohort is similar to that described internationally. Disclosures No relevant conflicts of interest to declare.

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