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Epilepsia Open Sep 2023Biallelic variants of RARS1, a gene that encodes the cytoplasmic tRNA synthetase for arginine (ArgRS), are associated with central nervous system (CNS) manifestations,... (Review)
Review
OBJECTIVE
Biallelic variants of RARS1, a gene that encodes the cytoplasmic tRNA synthetase for arginine (ArgRS), are associated with central nervous system (CNS) manifestations, such as hypomyelinating leukodystrophy-9 and developmental and epileptic encephalopathy (DEE). This study aimed to better understand the RARS1 biallelic mutations and the associated phenotypes, particularly in patients with DEE.
METHODS
We identified two patients with RARS1 biallelic mutations and functionally validated these mutations in vitro. Furthermore, we performed a review of the literature.
RESULTS
Two patients with hypomyelinating leukodystrophy were found to have RARS1 biallelic variants (Patient 1: c.1535G>A (p.Arg512Gln) and c.1382G>A (p.Arg461His); Patient 2: homozygous variants c.5A>T (p.Asp2Val)). Patient 2 had a severe clinical manifestation of DEE. A review of the literature identified 27 patients from five studies. Among the 29 patients, intellectual disability, developmental delay, and hypomyelination were the common symptoms, while 13 of them exhibited DEE and malformations of cortical development. Of the 25 variants identified, c.5A>G (p.Asp2Gly) was identified in 10 patients. ArgRS protein expression and stability were substantially reduced in the two newly identified patients.
SIGNIFICANCE
Patients with RARS1 biallelic mutations frequently exhibit DEE, a severe phenotype, along with hypomyelinating leukodystrophy. Besides its effects on the white matter, this mutation also influences cortical development. Moreover, the variants c.5A>T (p.Asp2Val), c.1382G>A (p.Arg461His), and c.1535G>A (p.Arg512Gln) are pathogenic and affect the expression of ArgRS by reducing the protein stability.
Topics: Humans; Mutation; Homozygote; Phenotype; Intellectual Disability; Brain Diseases
PubMed: 37186453
DOI: 10.1002/epi4.12751 -
Nature Communications Aug 2023Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic...
Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic colonies from 10 individuals with the inherited ribosomopathy Shwachman-Diamond syndrome to reconstruct haematopoietic phylogenies. In ~30% of colonies, we identify mutually exclusive mutations in TP53, EIF6, RPL5, RPL22, PRPF8, plus chromosome 7 and 15 aberrations that increase SBDS and EFL1 gene dosage, respectively. Target gene mutations commence in utero, resulting in a profusion of clonal expansions, with only a few haematopoietic stem cell lineages (mean 8, range 1-24) contributing ~50% of haematopoietic colonies across 8 individuals (range 4-100% clonality) by young adulthood. Rapid clonal expansion during disease transformation is associated with biallelic TP53 mutations and increased mutation burden. Our study highlights how convergent somatic mutation of the p53-dependent nucleolar surveillance pathway offsets the deleterious effects of germline ribosomopathy but increases opportunity for TP53-mutated cancer evolution.
Topics: Humans; Young Adult; Adult; Germ Cells; Chromosomes, Human, Pair 7; Gene Dosage; Hematopoietic Stem Cells; Mutation
PubMed: 37608017
DOI: 10.1038/s41467-023-40896-5 -
Trends in Molecular Medicine Jul 2023Cancer cells accumulate many genetic alterations throughout their lifetime, but only a few of them drive cancer progression, termed driver mutations. Driver mutations... (Review)
Review
Cancer cells accumulate many genetic alterations throughout their lifetime, but only a few of them drive cancer progression, termed driver mutations. Driver mutations may vary between cancer types and patients, can remain latent for a long time and become drivers at particular cancer stages, or may drive oncogenesis only in conjunction with other mutations. The high mutational, biochemical, and histological tumor heterogeneity makes driver mutation identification very challenging. In this review we summarize recent efforts to identify driver mutations in cancer and annotate their effects. We underline the success of computational methods to predict driver mutations in finding novel cancer biomarkers, including in circulating tumor DNA (ctDNA). We also report on the boundaries of their applicability in clinical research.
Topics: Humans; Neoplasms; Mutation; Carcinogenesis; Biomarkers, Tumor
PubMed: 37076339
DOI: 10.1016/j.molmed.2023.03.007 -
Genome Research Sep 2023The cytidine deaminases APOBEC3A (A3A) and APOBEC3B (A3B) are prominent mutators of human cancer genomes. However, tumor-specific genetic modulators of APOBEC-induced...
The cytidine deaminases APOBEC3A (A3A) and APOBEC3B (A3B) are prominent mutators of human cancer genomes. However, tumor-specific genetic modulators of APOBEC-induced mutagenesis are poorly defined. Here, we used a screen to identify 61 gene deletions that increase A3B-induced mutations in yeast. We also determined whether each deletion was epistatic with Ung1 loss, which indicated whether the encoded factors participate in the homologous recombination (HR)-dependent bypass of A3B/Ung1-dependent abasic sites or suppress A3B-catalyzed deamination by protecting against aberrant formation of single-stranded DNA (ssDNA). We found that the mutation spectra of A3B-induced mutations revealed genotype-specific patterns of strand-specific ssDNA formation and nucleotide incorporation across APOBEC-induced lesions. Combining these three metrics, we were able to establish a multifactorial signature of APOBEC-induced mutations specific to (1) failure to remove H3K56 acetylation, (2) defective CTF18-RFC complex function, and (3) defective HR-mediated bypass of APOBEC-induced lesions. We extended these results by analyzing mutation data for human tumors and found BRCA1/2-deficient breast cancers display three- to fourfold more APOBEC-induced mutations. Mirroring our results in yeast, Rev1-mediated C-to-G substitutions are mainly responsible for increased APOBEC-signature mutations in BRCA1/2-deficient tumors, and these mutations associate with lagging strand synthesis during replication. These results identify important factors that influence DNA replication dynamics and likely the abundance of APOBEC-induced mutation during tumor progression. They also highlight a novel role for BRCA1/2 during HR-dependent lesion bypass of APOBEC-induced lesions during cancer cell replication.
Topics: Humans; Female; BRCA1 Protein; Saccharomyces cerevisiae; BRCA2 Protein; Mutagenesis; Mutation; Cytidine Deaminase; Breast Neoplasms; Minor Histocompatibility Antigens
PubMed: 37532520
DOI: 10.1101/gr.277430.122 -
Nature Genetics Dec 2023Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. Using whole-genome...
Clonal hematopoiesis (CH) arises when a substantial proportion of mature blood cells is derived from a single hematopoietic stem cell lineage. Using whole-genome sequencing of 45,510 Icelandic and 130,709 UK Biobank participants combined with a mutational barcode method, we identified 16,306 people with CH. Prevalence approaches 50% in elderly participants. Smoking demonstrates a dosage-dependent impact on risk of CH. CH associates with several smoking-related diseases. Contrary to published claims, we find no evidence that CH is associated with cardiovascular disease. We provide evidence that CH is driven by genes that are commonly mutated in myeloid neoplasia and implicate several new driver genes. The presence and nature of a driver mutation alters the risk profile for hematological disorders. Nevertheless, most CH cases have no known driver mutations. A CH genome-wide association study identified 25 loci, including 19 not implicated previously in CH. Splicing, protein and expression quantitative trait loci were identified for CD164 and TCL1A.
Topics: Humans; Aged; Clonal Hematopoiesis; Genome-Wide Association Study; Hematopoiesis; Mutation; Hematopoietic Stem Cells
PubMed: 37932435
DOI: 10.1038/s41588-023-01555-z -
Cancer Science Jun 2024Deficient mismatch repair (dMMR) results in microsatellite instability (MSI), a pronounced mutator phenotype. High-frequency MSI (MSI-H)/dMMR is gaining increasing... (Review)
Review
Deficient mismatch repair (dMMR) results in microsatellite instability (MSI), a pronounced mutator phenotype. High-frequency MSI (MSI-H)/dMMR is gaining increasing interest as a biomarker for advanced cancer patients to determine their eligibility for immune checkpoint inhibitors (ICIs). Various methods based on next-generation sequencing (NGS) have been developed to assess the MSI status. Comprehensive genomic profiling (CGP) testing can precisely ascertain the MSI status as well as genomic alterations in a single NGS test. The MSI status can be also ascertained through the liquid biopsy-based CGP assays. MSI-H has thus been identified in various classes of tumors, resulting in a greater adoption of immunotherapy, which is hypothesized to be effective against malignancies that possess a substantial number of mutations and/or neoantigens. NGS-based studies have also characterized MSI-driven carcinogenesis, including significant rates of fusion kinases in colorectal cancers (CRCs) with MSI-H that are targets for therapeutic kinase inhibitors, particularly in MLH1-methylated CRCs with wild-type KRAS/BRAF. NTRK fusion is linked to the colorectal serrated neoplasia pathway. Recent advances in investigations of MSI-H malignancies have resulted in the development of novel diagnostic or therapeutic techniques, such as a synthetic lethal therapy that targets the Werner gene. DNA sensing in cancer cells is required for antitumor immunity induced by dMMR, opening up novel avenues and biomarkers for immunotherapy. Therefore, clinical relevance exists for analyses of MSI and MSI-H-associated genomic alterations in malignancy. In this article, we provide an update on MSI-driven carcinogenesis, with an emphasis on unique landscapes of diagnostic and immunotherapeutic strategies.
Topics: Humans; Microsatellite Instability; Neoplasms; High-Throughput Nucleotide Sequencing; DNA Mismatch Repair; Colorectal Neoplasms; Immune Checkpoint Inhibitors; Biomarkers, Tumor; Immunotherapy; Mutation
PubMed: 38528657
DOI: 10.1111/cas.16160 -
Journal of Cellular and Molecular... Sep 2023To date more than 1000 different variants in the PAH gene have been identified in patients with phenylketonuria (PKU). In Iran, several studies have been performed to... (Review)
Review
To date more than 1000 different variants in the PAH gene have been identified in patients with phenylketonuria (PKU). In Iran, several studies have been performed to investigate the genetics bases of the PKU in different parts of the country. In this study, we have analysed and present an update of the mutational landscape of the PAH gene as well as the population genetics and frequencies of detected variants for each cohort. Published articles on PKU mutations in Iran were identified through a comprehensive PubMed, Google Scholar, Web of Science (ISI), SCOPUS, Elsevier, Wiley Online Library and SID literature search using the terms: "phenylketonuria", "hyperphenylalaninemia", and "PKU" in combination with "Iran", "Iranian population", "mutation analysis", and "Molecular genetics". Among the literature-related to genetics of PKU, 18 studies were on the PKU mutations. According to these studies, in different populations of Iran 1497 patients were included for mutation detection that resulted in detection of 129 different mutations. Results of genetic analysis of the different cohorts of Iranian PKU patients show that the most prevalent mutation in Iran is the pathogenic splice variant c.1066-11G > A, occurring in 19.54% of alleles in the cohort. Four other common mutations were p.Arg261Gln, p.Pro281Leu, c.168 + 5G > C and p.Arg243Ter (8.18%, 6.45%, 5.88% and 3.7%, respectively). One notable feature of the studied populations is its high rate of consanguineous marriages. Considering this feature, determining the prevalent PKU mutations could be advantageous for designing screening and diagnostic panels in Iran.
Topics: Humans; Phenylalanine Hydroxylase; Iran; Gene Frequency; Phenylketonurias; Mutation; Genotype; DNA Mutational Analysis
PubMed: 37525467
DOI: 10.1111/jcmm.17865 -
Cell Reports Jul 2023The methyltransferase-like 3 (METTL3)-/METTL14-containing complex predominantly catalyzes N-methyladenosine (m6A) modification, which affects mRNA stability. Although...
The methyltransferase-like 3 (METTL3)-/METTL14-containing complex predominantly catalyzes N-methyladenosine (m6A) modification, which affects mRNA stability. Although the METTL14 R298P mutation is found in multiple cancer types, its biological effects are not completely understood. Here, we show that the heterozygous R298P mutation promotes cancer cell proliferation, whereas the homozygous mutation reduces proliferation. Methylated RNA immunoprecipitation sequencing analysis indicates that the R298P mutation reduces m6A modification at canonical motifs. Furthermore, this mutation induces m6A modification at aberrant motifs, which is evident only in cell lines harboring the homozygous mutation. The aberrant recognition of m6A modification sites alters the methylation efficiency at surrounding canonical motifs. One example is c-MET mRNA, which is highly methylated at canonical motifs close to the aberrantly methylated sites. Consequently, c-MET mRNA is severely destabilized, reducing c-Myc expression and suppressing cell proliferation. These data suggest that the METTL14 R298P mutation affects target recognition for m6A modification, perturbing gene expression patterns and cell growth.
Topics: Humans; Methyltransferases; Neoplasms; Cell Cycle; Cell Line; Mutation
PubMed: 37355987
DOI: 10.1016/j.celrep.2023.112688 -
International Journal of Molecular... Aug 2023V617F is the predominant driver mutation in patients with Philadelphia-negative myeloproliferative neoplasms (MPN). mutations are also frequent in clonal hematopoiesis... (Review)
Review
V617F is the predominant driver mutation in patients with Philadelphia-negative myeloproliferative neoplasms (MPN). mutations are also frequent in clonal hematopoiesis of indeterminate potential (CHIP) in otherwise "healthy" individuals. However, the period between mutation acquisition and MPN diagnosis (known as latency) varies widely between individuals, with mutations detectable several decades before diagnosis and even from birth in some individuals. Here, we will review the current evidence on the biological factors, such as additional mutations and chronic inflammation, which influence clonal expansion and may determine why some -mutated individuals will progress to an overt neoplasm during their lifetime while others will not. We will also introduce several germline variants that predispose individuals to CHIP (as well as MPN) identified from genome-wide association studies. Finally, we will explore possible mutation screening or interventions that could help to minimize MPN-associated cardiovascular complications or even delay malignant progression.
Topics: Humans; Early Detection of Cancer; Genome-Wide Association Study; Germ-Line Mutation; Myeloproliferative Disorders; Neoplasms
PubMed: 37628880
DOI: 10.3390/ijms241612700 -
PLoS Computational Biology Jul 2023Stochastic models of sequential mutation acquisition are widely used to quantify cancer and bacterial evolution. Across manifold scenarios, recurrent research questions...
Stochastic models of sequential mutation acquisition are widely used to quantify cancer and bacterial evolution. Across manifold scenarios, recurrent research questions are: how many cells are there with n alterations, and how long will it take for these cells to appear. For exponentially growing populations, these questions have been tackled only in special cases so far. Here, within a multitype branching process framework, we consider a general mutational path where mutations may be advantageous, neutral or deleterious. In the biologically relevant limiting regimes of large times and small mutation rates, we derive probability distributions for the number, and arrival time, of cells with n mutations. Surprisingly, the two quantities respectively follow Mittag-Leffler and logistic distributions regardless of n or the mutations' selective effects. Our results provide a rapid method to assess how altering the fundamental division, death, and mutation rates impacts the arrival time, and number, of mutant cells. We highlight consequences for mutation rate inference in fluctuation assays.
Topics: Humans; Mutation; Mutation Rate; Neoplasms; Probability; Bacteria; Models, Genetic
PubMed: 37428805
DOI: 10.1371/journal.pcbi.1011289