In Silico Analysis of Missense Mutations in LPAR6 Reveals Abnormal Phospholipid Signaling Pathway Leading to Hypotrichosis

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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In silico analysis of five missense mutations in CYP1B1 gene in Pakistani families affected with primary congenital glaucoma

International Ophthalmology ◽

10.1007/s10792-017-0508-4 ◽

2017 ◽

Vol 38 (2) ◽

pp. 807-814 ◽

Cited By ~ 2

Author(s):

Sabika Firasat ◽

Haiba Kaul ◽

Usman Ali Ashfaq ◽

Sobia Idrees

Keyword(s):

In Silico ◽

In Silico Analysis ◽

Congenital Glaucoma ◽

Missense Mutations ◽

Primary Congenital Glaucoma ◽

Cyp1b1 Gene ◽

Pakistani Families ◽

Silico Analysis

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Genetics A Comprehensive In Silico Analysis of Deleterious SNPs of Paraplegin Protein Associated with Hereditary Spastic Paraplegia through Mitochondrial Dysfunction

BioScientific Review ◽

10.32350/bsr.0202.01 ◽

2020 ◽

Vol 2 (2) ◽

pp. 1-14

Author(s):

Ammara Akhtar ◽

Sobia Nazir Choudhry ◽

Rana Muhammad Mateen ◽

Mureed Hussain

Keyword(s):

Hereditary Spastic Paraplegia ◽

In Silico ◽

Mitochondrial Protein ◽

In Silico Analysis ◽

Missense Mutations ◽

Spastic Paraplegia ◽

Bioinformatic Tools ◽

Pathogenic Variants ◽

Structural And Functional Properties ◽

Silico Analysis

Hereditary spastic paraplegia (HSP) is a heterogenous neurological disorder primarily associated with progressive spasticity. Paraplegin is a mitochondrial protein and mutations in this protein can lead to HSP. In this study, in silico analysis was carried out to identify the pathogenic variants of SPG7 (paraplegin protein). To find novel pathogenic mutations, missense and splicing variants were collected from gnomAD database and passed through a detailed and stringent analysis with the help of a variety of bioinformatic tools. The list of mutations was examined and compared in ClinVar. Altogether, 14 missense mutations and 18 splicing mutations were obtained and these mutations were predicted to have the potential of disrupting the normal structural and functional properties of paraplegin protein.

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In Silico Analysis of NF2 Gene Missense Mutations in Neurofibromatosis Type 2

Otology & Neurotology ◽

10.1097/mao.0000000000000639 ◽

2015 ◽

Vol 36 (5) ◽

pp. 908-914 ◽

Cited By ~ 4

Author(s):

Thomas E. Heineman ◽

D. Gareth R. Evans ◽

Fabien Campagne ◽

Samuel H. Selesnick

Keyword(s):

In Silico ◽

In Silico Analysis ◽

Neurofibromatosis Type ◽

Neurofibromatosis Type 2 ◽

Missense Mutations ◽

Nf2 Gene ◽

Silico Analysis

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In Silico Analysis of Missense Mutations as a First Step in Functional Studies: Examples from Two Sphingolipidoses

International Journal of Molecular Sciences ◽

10.3390/ijms19113409 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3409 ◽

Cited By ~ 2

Author(s):

Ana Duarte ◽

Diogo Ribeiro ◽

Luciana Moreira ◽

Olga Amaral

Keyword(s):

Amino Acid ◽

Protein Level ◽

In Silico ◽

In Silico Analysis ◽

Amino Acid Substitutions ◽

Missense Mutations ◽

Nucleotide Polymorphisms ◽

Functional Studies ◽

Analysis System ◽

Silico Analysis

In order to delineate a better approach to functional studies, we have selected 23 missense mutations distributed in different domains of two lysosomal enzymes, to be studied by in silico analysis. In silico analysis of mutations relies on computational modeling to predict their effects. Various computational platforms are currently available to check the probable causality of mutations encountered in patients at the protein and at the RNA levels. In this work we used four different platforms freely available online (Protein Variation Effect Analyzer- PROVEAN, PolyPhen-2, Swiss-model Expert Protein Analysis System—ExPASy, and SNAP2) to check amino acid substitutions and their effect at the protein level. The existence of functional studies, regarding the amino acid substitutions, led to the selection of the distinct protein mutants. Functional data were used to compare the results obtained with different bioinformatics tools. With the advent of next-generation sequencing, it is not feasible to carry out functional tests in all the variants detected. In silico analysis seems to be useful for the delineation of which mutants are worth studying through functional studies. Therefore, prediction of the mutation impact at the protein level, applying computational analysis, confers the means to rapidly provide a prognosis value to genotyping results, making it potentially valuable for patient care as well as research purposes. The present work points to the need to carry out functional studies in mutations that might look neutral. Moreover, it should be noted that single nucleotide polymorphisms (SNPs), occurring in coding and non-coding regions, may lead to RNA alterations and should be systematically verified. Functional studies can gain from a preliminary multi-step approach, such as the one proposed here.

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Corrigendum to “Hyperphenylalaninemia in the Czech Republic: genotype–phenotype correlations and in silico analysis of novel missense mutations” [Clin Chim Acta 419C: (2013) 1–10]

Clinica Chimica Acta ◽

10.1016/j.cca.2013.10.010 ◽

2013 ◽

Vol 426 ◽

pp. 157 ◽

Cited By ~ 1

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

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Evaluation role of miR-124 in neurodegenerative diseases: literature review and in silico analysis

10.1101/2021.10.17.464692 ◽

2021 ◽

Author(s):

Javad Amini ◽

Bahram Bibak ◽

Amir R Afshar ◽

Amirhossein Sahebkar

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Literature Review ◽

Neurodegenerative Diseases ◽

Signaling Pathway ◽

In Silico ◽

In Silico Analysis ◽

Rna Seq ◽

Silico Analysis

Neurodegenerative diseases (ND) are characterized by loss of function and structure of neurons. NDs like Alzheimer's disease (AD) and Parkinson's disease (PD) have high burden on the society and patients. Currently microRNAs (miRNAs) approach is growing. miRNAs express in different tissues, especially in the central neuron systems (CNS). miRNAs have a dynamic role in the CNS among this miRNAs, miR-124 significantly express in the CNS. Studies on miR-124 have shown that miR-124 improves ND. In this study, we evaluated the role of miR-124 in the ND by literature review and in silico analysis. We used Pubmed database to find miR-124 function in the Alzheimer's disease, Parkinson's disease, Multiple sclerosis, Huntington's disease and amyotrophic lateral sclerosis. To better understand the role of miR-124 in the neurons, RNA-seq data form miR-124-deleted neuronal cells extracted from GEO database and analyzed in Galaxy platform. According literature review miR-124 attenuates inflammation and apoptosis in the ND by target NF-kb signaling pathway and regulation of BAX/BCL-2. miR-124 targets BACE1 and decreases level of Aβ. RNA-seq data showed miR-124 downregulation, an increase in chemokine gene like CCL1 and cytokine-cytokine receptor-interaction, as well as MAPK-signaling pathway. Our study shows that miR-124 can be promising therapeutic approaches to ND.

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