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Asian Pacific Journal of Cancer... May 2022Familial adenomatous polyposis (FAP) is a hereditary disorder primarily caused by germline mutations in the APC gene. The most common type of mutation in the APC gene is...
BACKGROUND
Familial adenomatous polyposis (FAP) is a hereditary disorder primarily caused by germline mutations in the APC gene. The most common type of mutation in the APC gene is point mutation, while deletion mutation is much less frequent. The current study was conducted to investigate the mutation spectrum of the APC gene in Vietnamese FAP patients.
METHODS
Patients with the clinical diagnosis of FAP on colorectal endoscopy were screened for mutations in the APC gene using Sanger sequencing. Those who exhibited no point mutation subsequently underwent MLPA assay to detect deletion and duplication mutations. Besides, the relatives of patients with mutated APC genes were recruited for detecting carrier status.
RESULTS
Sixty-three patients with clinical colorectal polyposis were recruited. Mutations in the APC gene were detected in 26/63 patients (41.3%). Genetic analysis of 105 asymptomatic relatives of these 26 patients found mutations in the APC gene in 55 individuals (52.4%).
CONCLUSION
We successfully established the APC gene mutation spectrum in Vietnamese FAP patients for the first time. Of importance, we discovered two novel point mutations in the APC gene. The high prevalence of carrier status in asymptomatic family members of patients with mutation emphasizes the crucial role of appropriate genetic screening for early diagnosis, surveillance, and preventive measurements.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Asian People; Genes, APC; Humans; Mutation; Point Mutation; Vietnam
PubMed: 35633533
DOI: 10.31557/APJCP.2022.23.5.1517 -
BMC Bioinformatics Oct 2022RNA deleterious point mutation prediction was previously addressed with programs such as RNAmute and MultiRNAmute. The purpose of these programs is to predict a global...
BACKGROUND
RNA deleterious point mutation prediction was previously addressed with programs such as RNAmute and MultiRNAmute. The purpose of these programs is to predict a global conformational rearrangement of the secondary structure of a functional RNA molecule, thereby disrupting its function. RNAmute was designed to deal with only single point mutations in a brute force manner, while in MultiRNAmute an efficient approach to deal with multiple point mutations was developed. The approach used in MultiRNAmute is based on the stabilization of the suboptimal RNA folding prediction solutions and/or destabilization of the optimal folding prediction solution of the wild type RNA molecule. The MultiRNAmute algorithm is significantly more efficient than the brute force approach in RNAmute, but in the case of long sequences and large m-point mutation sets the MultiRNAmute becomes exponential in examining all possible stabilizing and destabilizing mutations.
RESULTS
An inherent limitation in the RNAmute and MultiRNAmute programs is their ability to predict only substitution mutations, as these programs were not designed to work with deletion or insertion mutations. To address this limitation we herein develop a very fast algorithm, based on suboptimal folding solutions, to predict a predefined number of multiple point deleterious mutations as specified by the user. Depending on the user's choice, each such set of mutations may contain combinations of deletions, insertions and substitution mutations. Additionally, we prove the hardness of predicting the most deleterious set of point mutations in structural RNAs.
CONCLUSIONS
We developed a method that extends our previous MultiRNAmute method to predict insertion and deletion mutations in addition to substitutions. The additional advantage of the new method is its efficiency to find a predefined number of deleterious mutations. Our new method may be exploited by biologists and virologists prior to site-directed mutagenesis experiments, which involve indel mutations along with substitutions. For example, our method may help to investigate the change of function in an RNA virus via mutations that disrupt important motifs in its secondary structure.
Topics: INDEL Mutation; Mutation; Point Mutation; RNA; Sequence Analysis, RNA
PubMed: 36241988
DOI: 10.1186/s12859-022-04943-0 -
Frontiers in Immunology 2022Major histocompatibility complex class II (MHC II) is an essential immune regulatory molecule that plays an important role in antigen presentation and T-cell...
Major histocompatibility complex class II (MHC II) is an essential immune regulatory molecule that plays an important role in antigen presentation and T-cell development. Abnormal MHC II expression can lead to immunodeficiency, clinically termed as type II bare lymphocyte syndrome (BLS), which usually results from mutations in the MHC II transactivator (CIITA) and other coactivators. Here, we present a new paradigm for MHC II deficiency in mice that involves a spontaneous point mutation on H2-Aa. A significantly reduced population of CD4 T cells was observed in mice obtained from the long-term homozygous breeding of (Map1, ) knockout mice; this phenotype was not attributed to the original knocked-out gene. MHC II expression was generally reduced, together with a marked deficiency of H2-Aa in the immune cells of these mice. Using cDNA and DNA sequencing, a spontaneous H2-Aa point mutation that led to false pre-mRNA splicing, deletion of eight bases in the mRNA, and protein frameshift was identified in these mice. These findings led to the discovery of a new type of spontaneous MHC II deficiency and provided a new paradigm to explain type II BLS in mice.
Topics: Animals; CD4-Positive T-Lymphocytes; Histocompatibility Antigens Class II; Mice; Mice, Knockout; Point Mutation; Severe Combined Immunodeficiency; T-Lymphocytes
PubMed: 35309308
DOI: 10.3389/fimmu.2022.810824 -
Methods in Cell Biology 2020The maternally inherited mitochondrial DNA (mtDNA) is a circular 16,569bp double stranded DNA that encodes 37 genes, 24 of which (2 rRNAs and 22 tRNAs) are necessary for...
The maternally inherited mitochondrial DNA (mtDNA) is a circular 16,569bp double stranded DNA that encodes 37 genes, 24 of which (2 rRNAs and 22 tRNAs) are necessary for transcription and translation of 13 polypeptides that are all subunits of respiratory chain. Pathogenic mutations in mtDNA cause respiratory chain dysfunction, and are the underlying defect in an ever-increasing number of mtDNA-related encephalomyopathies with distinct phenotypes. In this chapter, we present an overview of mtDNA mutations and describe the molecular techniques currently employed in our laboratory to detect two types of mtDNA mutations: single-large-scale rearrangements and point mutations.
Topics: DNA Mutational Analysis; DNA, Mitochondrial; Gene Rearrangement; Genome, Mitochondrial; High-Throughput Nucleotide Sequencing; Humans; Mutation; Point Mutation; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length
PubMed: 32183969
DOI: 10.1016/bs.mcb.2019.11.009 -
Microbial Pathogenesis Oct 2021Pasteurella multocida (P. multocida) is a Gram-negative bacterium which causes diseases in poultry, livestock, and humans, resulting in huge economic losses. P....
Pasteurella multocida (P. multocida) is a Gram-negative bacterium which causes diseases in poultry, livestock, and humans, resulting in huge economic losses. P. multocida serovar A CQ6 (PmCQ6) is a naturally occurring attenuated strain with a thin capsule. Thus, we aimed to explore why this strain is less virulent and produces less capsule compared with P. multocida serovar A strain CQ2 (PmCQ2). Analysis of capsular polysaccharide synthesis genes in PmCQ6 revealed that, compared with PmCQ2, there was only a single point mutation in the initiation codon sequence of the hyaC gene. To test whether this point mutation caused capsular deficiency and reduced virulence, we rescued this hyaC mutation and observed a restoration of capsule production and higher virulence. Transcriptome analysis showed that the hyaC point mutation led to a downregulation of capsule synthesis and/or iron utilization related-genes. Taken together, the results indicate that the start codon mutation of hyaC is an important factor affecting the capsule synthesis and virulence of PmCQ6.
Topics: Humans; Pasteurella Infections; Pasteurella multocida; Point Mutation; Serogroup; Uridine Diphosphate Glucose Dehydrogenase; Virulence
PubMed: 34411653
DOI: 10.1016/j.micpath.2021.105145 -
Genes Sep 2023Large musculoaponeurotic fibrosarcoma (MAF) transcription factors contain acidic, basic, and leucine zipper regions. Four types of MAF have been elucidated in mice and... (Review)
Review
Large musculoaponeurotic fibrosarcoma (MAF) transcription factors contain acidic, basic, and leucine zipper regions. Four types of MAF have been elucidated in mice and humans, namely c-MAF, MAFA, MAFB, and NRL. This review aimed to elaborate on the functions of MAF transcription factors that have been studied in vivo so far, as well as describe the pathology of human patients and corresponding mouse models with c-MAF, MAFA, and MAFB point mutations. To identify the functions of MAF transcription factors in vivo, we generated genetically modified mice lacking c-MAF, MAFA, and MAFB and analyzed their phenotypes. Further, in recent years, c-MAF, MAFA, and MAFB have been identified as causative genes underpinning many rare diseases. Careful observation of human patients and animal models is important to examine the pathophysiological mechanisms underlying these conditions for targeted therapies. Murine models exhibit phenotypes similar to those of human patients with c-MAF, MAFA, and MAFB mutations. Therefore, generating these animal models emphasizes their usefulness for research uncovering the pathophysiology of point mutations in MAF transcription factors and the development of etiology-based therapies.
Topics: Humans; Mice; Animals; Transcription Factors; Maf Transcription Factors, Large; MafB Transcription Factor; Insulin; Point Mutation
PubMed: 37895232
DOI: 10.3390/genes14101883 -
Cardiovascular Research Feb 2024
Topics: Humans; Myocytes, Cardiac; Ryanodine Receptor Calcium Release Channel; Calcium; Point Mutation; Excitation Contraction Coupling
PubMed: 38198240
DOI: 10.1093/cvr/cvad193 -
Methods in Molecular Biology (Clifton,... 2024Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system has been developed as a robust genome engineering tool in a variety of organisms...
Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system has been developed as a robust genome engineering tool in a variety of organisms attributed to its high efficiency and versatility. In this chapter, we described the detailed procedures of CRISPR-Cas9-based genetic manipulation in Pseudomonas aeruginosa, including precise gene deletion and insertion via Cas9-mediated DNA double-strand break and homologous recombination repair. In addition, we provided a detailed protocol for cytidine base editor, a highly efficient gene inactivation and point mutation tool in Pseudomonas aeruginosa.
Topics: Gene Editing; CRISPR-Cas Systems; Pseudomonas aeruginosa; Point Mutation; Recombinational DNA Repair
PubMed: 37819511
DOI: 10.1007/978-1-0716-3473-8_1 -
Frontiers in Cellular and Infection... 2022Mutations may produce highly transmissible and damaging HIV variants, which increase the genetic diversity, and pose a challenge to develop vaccines. Therefore, it is of...
Mutations may produce highly transmissible and damaging HIV variants, which increase the genetic diversity, and pose a challenge to develop vaccines. Therefore, it is of great significance to understand how mutations drive the virulence of HIV. Based on the 11897 reliable genomes of HIV-1 retrieved from HIV sequence Database, we analyze the 12 types of point mutation (A>C, A>G, A>T, C>A, C>G, C>T, G>A, G>C, G>T, T>A, T>C, T>G) from multiple statistical perspectives for the first time. The global/geographical location/subtype/k-mer analysis results report that A>G, G>A, C>T and T>C account for nearly 64% among all SNPs, which suggest that APOBEC-editing and ADAR-editing may play an important role in HIV-1 infectivity. Time analysis shows that most genomes with abnormal mutation numbers comes from African countries. Finally, we use natural vector method to check the k-mer distribution changing patterns in the genome, and find that there is an important substitution pattern between nucleotides A and G, and 2-mer CG may have a significant impact on viral infectivity. This paper provides an insight into the single mutation of HIV-1 by using the latest data in the HIV sequence Database.
Topics: HIV-1; Point Mutation; Mutation; Mutation, Missense; Databases, Nucleic Acid
PubMed: 36457853
DOI: 10.3389/fcimb.2022.1033481 -
Protein Science : a Publication of the... Jan 2021Predicting the effect of missense variations on protein stability and dynamics is important for understanding their role in diseases, and the link between protein...
Predicting the effect of missense variations on protein stability and dynamics is important for understanding their role in diseases, and the link between protein structure and function. Approaches to estimate these changes have been proposed, but most only consider single-point missense variants and a static state of the protein, with those that incorporate dynamics are computationally expensive. Here we present DynaMut2, a web server that combines Normal Mode Analysis (NMA) methods to capture protein motion and our graph-based signatures to represent the wildtype environment to investigate the effects of single and multiple point mutations on protein stability and dynamics. DynaMut2 was able to accurately predict the effects of missense mutations on protein stability, achieving Pearson's correlation of up to 0.72 (RMSE: 1.02 kcal/mol) on a single point and 0.64 (RMSE: 1.80 kcal/mol) on multiple-point missense mutations across 10-fold cross-validation and independent blind tests. For single-point mutations, DynaMut2 achieved comparable performance with other methods when predicting variations in Gibbs Free Energy (ΔΔG) and in melting temperature (ΔT ). We anticipate our tool to be a valuable suite for the study of protein flexibility analysis and the study of the role of variants in disease. DynaMut2 is freely available as a web server and API at http://biosig.unimelb.edu.au/dynamut2.
Topics: Internet; Mutation, Missense; Point Mutation; Protein Stability; Proteins; Software
PubMed: 32881105
DOI: 10.1002/pro.3942