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Molecular Genetics & Genomic Medicine Dec 2021Thalassemia is an inherited hematological disorder categorized by a decrease or absence of one or more of the globin chains synthesis. Beta-thalassemia is caused by one... (Review)
Review
BACKGROUND
Thalassemia is an inherited hematological disorder categorized by a decrease or absence of one or more of the globin chains synthesis. Beta-thalassemia is caused by one or more mutations in the beta-globin gene. The absence or reduced amount of beta-globin chains causes ineffective erythropoiesis which leads to anemia.
METHODS
Beta-thalassemia has been further divided into three main forms: thalassemia major, intermedia, and minor/silent carrier. A more severe form among these is thalassemia major in which individuals depend upon blood transfusion for survival. The high level of iron deposition occurs due to regular blood transfusion therapy.
RESULTS
Overloaded iron raises the synthesis of reactive oxygen species (ROS) that are noxious and prompting the injury to the hepatic, endocrine, and vascular system. Thalassemia can be analyzed and diagnosed via prenatal testing (genetic testing of amniotic fluid), blood smear, complete blood count, and DNA analysis (genetic testing). Treatment of thalassemia intermediate is symptomatic; however; it can also be accomplished by folic supplementation and splenectomy.
CONCLUSION
Thalassemia major can be cured through regular transfusion of blood, transplantation of bone marrow, iron chelation management, hematopoietic stem cell transplantation, stimulation of fetal hemoglobin production, and gene therapy.
Topics: Alleles; Animals; Clinical Decision-Making; Combined Modality Therapy; Disease Management; Disease Susceptibility; Genetic Testing; Genotype; Humans; Incidence; Mutation; Phenotype; Prevalence; Prognosis; Severity of Illness Index; Treatment Outcome; beta-Globins; beta-Thalassemia
PubMed: 34738740
DOI: 10.1002/mgg3.1788 -
Cell Oct 2021While prime editing enables precise sequence changes in DNA, cellular determinants of prime editing remain poorly understood. Using pooled CRISPRi screens, we discovered...
While prime editing enables precise sequence changes in DNA, cellular determinants of prime editing remain poorly understood. Using pooled CRISPRi screens, we discovered that DNA mismatch repair (MMR) impedes prime editing and promotes undesired indel byproducts. We developed PE4 and PE5 prime editing systems in which transient expression of an engineered MMR-inhibiting protein enhances the efficiency of substitution, small insertion, and small deletion prime edits by an average 7.7-fold and 2.0-fold compared to PE2 and PE3 systems, respectively, while improving edit/indel ratios by 3.4-fold in MMR-proficient cell types. Strategic installation of silent mutations near the intended edit can enhance prime editing outcomes by evading MMR. Prime editor protein optimization resulted in a PEmax architecture that enhances editing efficacy by 2.8-fold on average in HeLa cells. These findings enrich our understanding of prime editing and establish prime editing systems that show substantial improvement across 191 edits in seven mammalian cell types.
Topics: CRISPR-Cas Systems; Cell Line; DNA; DNA Mismatch Repair; Female; Gene Editing; Genes, Dominant; Genome, Human; Humans; Male; Models, Biological; MutL Protein Homolog 1; Mutation; RNA; Reproducibility of Results
PubMed: 34653350
DOI: 10.1016/j.cell.2021.09.018 -
Heart (British Cardiac Society) Mar 2022Congenital long QT syndrome (LQTS) is characterised by heart rate corrected QT interval prolongation and life-threatening arrhythmias, leading to syncope and sudden... (Review)
Review
Congenital long QT syndrome (LQTS) is characterised by heart rate corrected QT interval prolongation and life-threatening arrhythmias, leading to syncope and sudden death. Variations in genes encoding for cardiac ion channels, accessory ion channel subunits or proteins modulating the function of the ion channel have been identified as disease-causing mutations in up to 75% of all LQTS cases. Based on the underlying genetic defect, LQTS has been subdivided into different subtypes. Growing insights into the genetic background and pathophysiology of LQTS has led to the identification of genotype-phenotype relationships for the most common genetic subtypes, the recognition of genetic and non-genetic modifiers of phenotype, optimisation of risk stratification algorithms and the discovery of gene-specific therapies in LQTS. Nevertheless, despite these great advancements in the LQTS field, large gaps in knowledge still exist. For example, up to 25% of LQTS cases still remain genotype elusive, which hampers proper identification of family members at risk, and it is still largely unknown what determines the large variability in disease severity, where even within one family an identical mutation causes malignant arrhythmias in some carriers, while in other carriers, the disease is clinically silent. In this review, we summarise the current evidence available on the diagnosis, clinical management and therapeutic strategies in LQTS. We also discuss new scientific developments and areas of research, which are expected to increase our understanding of the complex genetic architecture in genotype-negative patients, lead to improved risk stratification in asymptomatic mutation carriers and more targeted (gene-specific and even mutation-specific) therapies.
Topics: Arrhythmias, Cardiac; Electrocardiography; Genetic Testing; Genotype; Humans; Ion Channels; Long QT Syndrome; Mutation; Phenotype
PubMed: 34039680
DOI: 10.1136/heartjnl-2020-318259 -
Cancer Cell Jan 2020Pituitary neuroendocrine tumors (PitNETs) are common, with five main histological subtypes: lactotroph, somatotroph, and thyrotroph (POU1F1/PIT1 lineage); corticotroph...
Pituitary neuroendocrine tumors (PitNETs) are common, with five main histological subtypes: lactotroph, somatotroph, and thyrotroph (POU1F1/PIT1 lineage); corticotroph (TBX19/TPIT lineage); and gonadotroph (NR5A1/SF1 lineage). We report a comprehensive pangenomic classification of PitNETs. PitNETs from POU1F1/PIT1 lineage showed an epigenetic signature of diffuse DNA hypomethylation, with transposable elements expression and chromosomal instability (except for GNAS-mutated somatotrophs). In TPIT lineage, corticotrophs were divided into three classes: the USP8-mutated with overt secretion, the USP8-wild-type with increased invasiveness and increased epithelial-mesenchymal transition, and the large silent tumors with gonadotroph transdifferentiation. Unexpected expression of gonadotroph markers was also found in GNAS-wild-type somatotrophs (SF1 expression), challenging the current definition of SF1/gonadotroph lineage. This classification improves our understanding and affects the clinical stratification of patients with PitNETs.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cell Lineage; Chromosome Aberrations; DNA Methylation; Endopeptidases; Endosomal Sorting Complexes Required for Transport; Epigenesis, Genetic; Epigenome; Exome; Female; Humans; Male; Middle Aged; Mutation; Neoplasm Invasiveness; Neuroendocrine Tumors; Pituitary Gland; Pituitary Neoplasms; Prognosis; Transcriptome; Ubiquitin Thiolesterase; Young Adult
PubMed: 31883967
DOI: 10.1016/j.ccell.2019.11.002 -
Brain & Development Jan 2021Angelman Syndrome (AS) is characterized by severe developmental delays including marked speech impairment, movement abnormalities(ataxia, tremor), and unique behaviors... (Review)
Review
Angelman Syndrome (AS) is characterized by severe developmental delays including marked speech impairment, movement abnormalities(ataxia, tremor), and unique behaviors such as frequent laughter and is caused by dysfunctional maternal UBE3A gene (maternal 15q11-13 deletions, maternal specific UBE3A mutation, uniparental disomy, and imprinting defect). Intractable epileptic seizures since early childhood with characteristic EEG abnormalities are present in 80-90% patients with AS. Underlying pathophysiology may involve neocortical and thalamocortical hyperexcitability secondary to severe reduction of GABAergic input, as well as dysfunctional synaptic plasticity, deficient synaptogenesis, and neuronal morphological immaturity. The onset of epilepsy is most prevalent between 1 and 3 years of age; however, approximately 25% of patients developed epilepsy before one year of age. Various types of generalized seizures are most prevalent, with most common types are myoclonic and atypical absence.More than 95% of epilepsy patients may have daily seizures at least for a limited time during early childhood, and two-third patients develop disabling seizures. Fever provoked seizures, and frequent occurrence of nonconvulsive status epilepticus are two unique features. Seizures are frequently pharmacoresistant. Considering underlying prominent GABAergic dysfunction, clinicians had used AEDs that target GABAergic signaling such as valproate, phenobarbital, and clonazepam as first-line therapies for AS. However, due to the unfavorable side effect profile of these AEDs, a recent treatment approach involves priority use of levetiracetam, clobazam, topiramate, lamotrigine, ethosuximide, VNS, and carbohydrate-restricted diets. Besides symptomatic management, there has been recent progress to find a curative treatment with the following approaches: 1. Gene/protein replacement therapy (Adeno and lentiviral vector therapy to deliver a gene or secretory protein); 2. Activation of the intact but silent paternal copy of UBE3A (antisense oligonucleotide therapy and artificial transcription factors); and 3. Downstream therapies (OV101/gaboxadol, ketone supplement, novel compounds/peptides, anti-inflammatory/regenerative therapy).
Topics: Angelman Syndrome; Anticonvulsants; Child; Child, Preschool; Electroencephalography; Epilepsy; Female; Humans; Infant; Infant, Newborn; Male; Seizures; Status Epilepticus; Ubiquitin-Protein Ligases; Valproic Acid
PubMed: 32893075
DOI: 10.1016/j.braindev.2020.08.014 -
Blood Feb 2022Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying... (Observational Study)
Observational Study
Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and in genetically modified mouse models, and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.
Topics: Aged; Animals; Female; Humans; Male; Mice; Middle Aged; Chromosome Aberrations; Immunophenotyping; Lymphoma, B-Cell, Marginal Zone; Multigene Family; Mutation; Spleen; Splenic Neoplasms; Transcriptome; Tumor Microenvironment
PubMed: 34653238
DOI: 10.1182/blood.2021012386 -
Nature Jun 2022Synonymous mutations in protein-coding genes do not alter protein sequences and are thus generally presumed to be neutral or nearly neutral. Here, to experimentally...
Synonymous mutations in protein-coding genes do not alter protein sequences and are thus generally presumed to be neutral or nearly neutral. Here, to experimentally verify this presumption, we constructed 8,341 yeast mutants each carrying a synonymous, nonsynonymous or nonsense mutation in one of 21 endogenous genes with diverse functions and expression levels and measured their fitness relative to the wild type in a rich medium. Three-quarters of synonymous mutations resulted in a significant reduction in fitness, and the distribution of fitness effects was overall similar-albeit nonidentical-between synonymous and nonsynonymous mutations. Both synonymous and nonsynonymous mutations frequently disturbed the level of mRNA expression of the mutated gene, and the extent of the disturbance partially predicted the fitness effect. Investigations in additional environments revealed greater across-environment fitness variations for nonsynonymous mutants than for synonymous mutants despite their similar fitness distributions in each environment, suggesting that a smaller proportion of nonsynonymous mutants than synonymous mutants are always non-deleterious in a changing environment to permit fixation, potentially explaining the common observation of substantially lower nonsynonymous than synonymous substitution rates. The strong non-neutrality of most synonymous mutations, if it holds true for other genes and in other organisms, would require re-examination of numerous biological conclusions about mutation, selection, effective population size, divergence time and disease mechanisms that rely on the assumption that synoymous mutations are neutral.
Topics: Amino Acid Sequence; Codon, Nonsense; Evolution, Molecular; Genes, Fungal; Genetic Fitness; Mutation Rate; RNA, Fungal; RNA, Messenger; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Selection, Genetic; Silent Mutation
PubMed: 35676473
DOI: 10.1038/s41586-022-04823-w -
Nature Dec 2019The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens. These microorganisms have a highly restrictive permeability...
The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens. These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds. As a result, the last class of antibiotics that acted against Gram-negative bacteria was developed in the 1960s. We reason that useful compounds can be found in bacteria that share similar requirements for antibiotics with humans, and focus on Photorhabdus symbionts of entomopathogenic nematode microbiomes. Here we report a new antibiotic that we name darobactin, which was obtained using a screen of Photorhabdus isolates. Darobactin is coded by a silent operon with little production under laboratory conditions, and is ribosomally synthesized. Darobactin has an unusual structure with two fused rings that form post-translationally. The compound is active against important Gram-negative pathogens both in vitro and in animal models of infection. Mutants that are resistant to darobactin map to BamA, an essential chaperone and translocator that folds outer membrane proteins. Our study suggests that bacterial symbionts of animals contain antibiotics that are particularly suitable for development into therapeutics.
Topics: Animals; Anti-Bacterial Agents; Bacterial Outer Membrane Proteins; Cell Line; Disease Models, Animal; Drug Discovery; Drug Resistance, Microbial; Escherichia coli Proteins; Female; Gastrointestinal Microbiome; Gram-Negative Bacteria; Humans; Mice; Microbial Sensitivity Tests; Microbial Viability; Mutation; Nematoda; Operon; Phenylpropionates; Photorhabdus; Substrate Specificity; Symbiosis
PubMed: 31747680
DOI: 10.1038/s41586-019-1791-1 -
Genes Oct 2023Hereditary thrombotic thrombocytopenic purpura (hTTP), also known as Upshaw-Schulman syndrome, is a rare genetic disorder caused by mutations in the ADAMTS13 gene that... (Review)
Review
Hereditary thrombotic thrombocytopenic purpura (hTTP), also known as Upshaw-Schulman syndrome, is a rare genetic disorder caused by mutations in the ADAMTS13 gene that leads to decreased or absent production of the plasma von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS13. The result is circulating ultra-large multimers of VWF that can cause microthrombi, intravascular occlusion and organ damage, especially at times of turbulent circulation. Patients with hTTP may have many overt or clinically silent manifestations, and a high index of suspicion is required for diagnosis. For the treatment of hTTP, the goal is simply replacement of ADAMTS13. The primary treatment is prophylaxis with plasma infusions or plasma-derived factor VIII products, providing sufficient ADAMTS13 to prevent acute episodes. When acute episodes occur, prophylaxis is intensified. Recombinant ADAMTS13, which is near to approval, will immediately be the most effective and also the most convenient treatment. In this review, we discuss the possible clinical manifestations of this rare disease and the relevant differential diagnoses in different age groups. An extensive discussion on prophylaxis and treatment strategies is also presented. Unique real patient cases have been added to highlight critical aspects of hTTP manifestations, diagnosis and treatment.
Topics: Humans; Purpura, Thrombotic Thrombocytopenic; von Willebrand Factor; ADAM Proteins; Mutation; Diagnosis, Differential
PubMed: 37895305
DOI: 10.3390/genes14101956