-
Journal of Neurogenetics 2023is a gene whose alternative splicing yields epithelial, neuronal, and muscular isoforms. The autosomal recessive () spontaneous mouse mutation causes degeneration of... (Review)
Review
is a gene whose alternative splicing yields epithelial, neuronal, and muscular isoforms. The autosomal recessive () spontaneous mouse mutation causes degeneration of spinocerebellar tracts as well as peripheral sensory nerves, dorsal root ganglia, and cranial nerve ganglia. In addition to mutants, axonopathy and neurofilament accumulation in perikarya are features of two other murine lines with spontaneous mutations, targeted knockout mice, Tg4 transgenic mice carrying two deleted exons, mice with trapped actin-binding domain-containing isoforms, and conditional Schwann cell-specific knockout mice. As a result of nerve damage, mutants display dystonia and ataxia, as seen in several genetically modified models and their motor coordination deficits have been quantified along with the spontaneous nonsense mutant, the conditional Schwann cell-specific knockout, the conditional mutant, and the Dst-b isoform specific mutant. Recent findings in humans have associated mutations of the Dst-b isoform with hereditary sensory and autonomic neuropathies type 6 (HSAN-VI). These data should further encourage the development of genetic techniques to treat or prevent ataxic and dystonic symptoms.
Topics: Animals; Humans; Mice; Dystonia; Mice, Knockout; Mice, Transgenic; Neurobiology; Neurons; Protein Isoforms
PubMed: 38465459
DOI: 10.1080/01677063.2024.2319880 -
Hereditas Mar 2024Mutants have had a fundamental impact upon scientific and applied genetics. They have paved the way for the molecular and genomic era, and most of today's crop plants... (Review)
Review
BACKGROUND
Mutants have had a fundamental impact upon scientific and applied genetics. They have paved the way for the molecular and genomic era, and most of today's crop plants are derived from breeding programs involving mutagenic treatments.
RESULTS
Barley (Hordeum vulgare L.) is one of the most widely grown cereals in the world and has a long history as a crop plant. Barley breeding started more than 100 years ago and large breeding programs have collected and generated a wide range of natural and induced mutants, which often were deposited in genebanks around the world. In recent years, an increased interest in genetic diversity has brought many historic mutants into focus because the collections are regarded as valuable resources for understanding the genetic control of barley biology and barley breeding. The increased interest has been fueled also by recent advances in genomic research, which provided new tools and possibilities to analyze and reveal the genetic diversity of mutant collections.
CONCLUSION
Since detailed knowledge about phenotypic characters of the mutants is the key to success of genetic and genomic studies, we here provide a comprehensive description of mostly morphological barley mutants. The review is closely linked to the International Database for Barley Genes and Barley Genetic Stocks ( bgs.nordgen.org ) where further details and additional images of each mutant described in this review can be found.
Topics: Hordeum; Plant Breeding; Mutagenesis; Genomics
PubMed: 38454479
DOI: 10.1186/s41065-023-00304-w -
Neural Regeneration Research Oct 2023Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein, a type III intermediate filament protein expressed in... (Review)
Review
Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein, a type III intermediate filament protein expressed in astrocytes. Both early (infantile or juvenile) and adult onsets of the disease are known and, in both cases, astrocytes present characteristic aggregates, named Rosenthal fibers. Mutations are spread along the glial fibrillary acidic protein sequence disrupting the typical filament network in a dominant manner. Although the presence of aggregates suggests a proteostasis problem of the mutant forms, this behavior is also observed when the expression of wild-type glial fibrillary acidic protein is increased. Additionally, several isoforms of glial fibrillary acidic protein have been described to date, while the impact of the mutations on their expression and proportion has not been exhaustively studied. Moreover, the posttranslational modification patterns and/or the protein-protein interaction networks of the glial fibrillary acidic protein mutants may be altered, leading to functional changes that may modify the morphology, positioning, and/or the function of several organelles, in turn, impairing astrocyte normal function and subsequently affecting neurons. In particular, mitochondrial function, redox balance and susceptibility to oxidative stress may contribute to the derangement of glial fibrillary acidic protein mutant-expressing astrocytes. To study the disease and to develop putative therapeutic strategies, several experimental models have been developed, a collection that is in constant growth. The fact that most cases of Alexander disease can be related to glial fibrillary acidic protein mutations, together with the availability of new and more relevant experimental models, holds promise for the design and assay of novel therapeutic strategies.
PubMed: 37056123
DOI: 10.4103/1673-5374.369097 -
Molecular Psychiatry Sep 2023Despite intensive studies in modeling neuropsychiatric disorders especially autism spectrum disorder (ASD) in animals, many challenges remain. Genetic mutant mice have...
Despite intensive studies in modeling neuropsychiatric disorders especially autism spectrum disorder (ASD) in animals, many challenges remain. Genetic mutant mice have contributed substantially to the current understanding of the molecular and neural circuit mechanisms underlying ASD. However, the translational value of ASD mouse models in preclinical studies is limited to certain aspects of the disease due to the apparent differences in brain and behavior between rodents and humans. Non-human primates have been used to model ASD in recent years. However, a low reproduction rate due to a long reproductive cycle and a single birth per pregnancy, and an extremely high cost prohibit a wide use of them in preclinical studies. Canine model is an appealing alternative because of its complex and effective dog-human social interactions. In contrast to non-human primates, dog has comparable drug metabolism as humans and a high reproduction rate. In this study, we aimed to model ASD in experimental dogs by manipulating the Shank3 gene as SHANK3 mutations are one of most replicated genetic defects identified from ASD patients. Using CRISPR/Cas9 gene editing, we successfully generated and characterized multiple lines of Beagle Shank3 (bShank3) mutants that have been propagated for a few generations. We developed and validated a battery of behavioral assays that can be used in controlled experimental setting for mutant dogs. bShank3 mutants exhibited distinct and robust social behavior deficits including social withdrawal and reduced social interactions with humans, and heightened anxiety in different experimental settings (n = 27 for wild-type controls and n = 44 for mutants). We demonstrate the feasibility of producing a large number of mutant animals in a reasonable time frame. The robust and unique behavioral findings support the validity and value of a canine model to investigate the pathophysiology and develop treatments for ASD and potentially other psychiatric disorders.
Topics: Animals; Dogs; Humans; Autism Spectrum Disorder; CRISPR-Cas Systems; Disease Models, Animal; Gene Editing; Microfilament Proteins; Nerve Tissue Proteins
PubMed: 37848710
DOI: 10.1038/s41380-023-02276-9 -
Bioscience, Biotechnology, and... Sep 2023Gibberellins (GAs) are plant hormones with a tetracyclic diterpenoid structure that are involved in various important developmental processes. Two GA-deficient mutants...
Gibberellins (GAs) are plant hormones with a tetracyclic diterpenoid structure that are involved in various important developmental processes. Two GA-deficient mutants were isolated: a semidwarf mutant "sd1", which was found to have a defective GA20ox2 gene and was introduced to the world in a green revolution cultivar, and a severe dwarf allele of "d18", with a defective GA3ox2 gene. Based on the phenotypic similarity of d18, rice dwarf mutants were screened, further classifying them into GA-sensitive and GA-insensitive by applying exogenous GA3. Finally, GA-deficient rice mutants at 6 different loci and 3 GA signaling mutants (gid1, gid2, and slr1) were isolated. The GID1 gene encodes a GA nuclear receptor, and the GID1-DELLA (SLR1) system for GA perception is widely used in vascular plants. The structural characteristics of GID1 and GA metabolic enzymes have also been reviewed.
Topics: Gibberellins; Plant Proteins; Plant Growth Regulators; Signal Transduction; Oryza; Gene Expression Regulation, Plant
PubMed: 37403377
DOI: 10.1093/bbb/zbad090 -
Nature Communications Oct 2023The literature about mutant invasion and fixation typically assumes populations to exist in isolation from their ecosystem. Yet, populations are part of ecological...
The literature about mutant invasion and fixation typically assumes populations to exist in isolation from their ecosystem. Yet, populations are part of ecological communities, and enemy-victim (e.g. predator-prey or pathogen-host) interactions are particularly common. We use spatially explicit, computational pathogen-host models (with wild-type and mutant hosts) to re-visit the established theory about mutant fixation, where the pathogen equally attacks both wild-type and mutant individuals. Mutant fitness is assumed to be unrelated to infection. We find that pathogen presence substantially weakens selection, increasing the fixation probability of disadvantageous mutants and decreasing it for advantageous mutants. The magnitude of the effect rises with the infection rate. This occurs because infection induces spatial structures, where mutant and wild-type individuals are mostly spatially separated. Thus, instead of mutant and wild-type individuals competing with each other, it is mutant and wild-type "patches" that compete, resulting in smaller fitness differences and weakened selection. This implies that the deleterious mutant burden in natural populations might be higher than expected from traditional theory.
Topics: Humans; Models, Biological; Ecosystem; Probability; Population Dynamics
PubMed: 37863909
DOI: 10.1038/s41467-023-41787-5 -
The New Phytologist Sep 2023Plant transpiration is controlled by stomata, with S- and R-type anion channels playing key roles in guard cell action. Arabidopsis mutants lacking the ALMT12/QUAC1...
Plant transpiration is controlled by stomata, with S- and R-type anion channels playing key roles in guard cell action. Arabidopsis mutants lacking the ALMT12/QUAC1 R-type anion channel function in guard cells show only a partial reduction in R-type channel currents. The molecular nature of these remaining R-type anion currents is still unclear. To further elucidate this, patch clamp, transcript and gas-exchange measurements were performed with wild-type (WT) and different almt mutant plants. The R-type current fraction in the almt12 mutant exhibited the same voltage dependence, susceptibility to ATP block and lacked a chloride permeability as the WT. Therefore, we asked whether the R-type anion currents in the ALMT12/QUAC1-free mutant are caused by additional ALMT isoforms. In WT guard cells, ALMT12, ALMT13 and ALMT14 transcripts were detected, whereas only ALMT13 was found expressed in the almt12 mutant. Substantial R-type anion currents still remained active in the almt12/13 and almt12/14 double mutants as well as the almt12/13/14 triple mutant. In good agreement, CO -triggered stomatal closure required the activity of ALMT12 but not ALMT13 or ALMT14. The results suggest that, with the exception of ALMT12, channel species other than ALMTs carry the guard cell R-type anion currents.
Topics: Arabidopsis Proteins; Plant Stomata; Arabidopsis; Anions; Abscisic Acid
PubMed: 37434346
DOI: 10.1111/nph.19124 -
Current Drug Research Reviews Aug 2023Brain-derived neurotrophic factor (BDNF) has been proposed as a treatment for neurodegeneration, including diseases of the cerebellum, where BDNF levels or those of its...
Brain-derived neurotrophic factor (BDNF) has been proposed as a treatment for neurodegeneration, including diseases of the cerebellum, where BDNF levels or those of its main receptor, TrkB, are often diminished relative to controls, thereby serving as replacement therapy. Experimental evidence indicates that BDNF signaling countered cerebellar degeneration, sensorimotor deficits, or both, in transgenic ATXN1 mice mutated for ataxin-1, Cacna1a knock-in mice mutated for ataxin-6, mice injected with lentivectors encoding RNA sequences against human FXN into the cerebellar cortex, Kcnj6Wv (Weaver) mutant mice with granule cell degeneration, and rats with olivocerebellar transaction, similar to a BDNF-overexpressing transgenic line interbred with Cacng2stg mutant mice. In this regard, this study discusses whether BDNF is effective in cerebellar pathologies where BDNF levels are normal and whether it is effective in cases with combined cerebellar and basal ganglia damage.
PubMed: 37609676
DOI: 10.2174/2589977515666230811093021 -
Trends in Biochemical Sciences May 2024Benbarche, Pineda, Galvis, et al. delineate an essential role for the G-patch motif-containing protein GPATCH8 in mis-splicing associated with cancer-driving mutations...
Benbarche, Pineda, Galvis, et al. delineate an essential role for the G-patch motif-containing protein GPATCH8 in mis-splicing associated with cancer-driving mutations of the splicing factor SF3B1. GPATCH8 cooperates with SF3B1 mutants, affecting the splicing machinery. Targeting GPATCH8 reveals therapeutic opportunities for SF3B1 mutant cancers and other splicing-related diseases.
PubMed: 38762373
DOI: 10.1016/j.tibs.2024.05.001 -
Cancer Research Sep 2023Oncogenic point mutants of isocitrate dehydrogenases 1 and 2 (IDH2) generate 2-hydroxyglutarate, which inhibits lysine demethylases and increases heterochromatin. Tumor...
Oncogenic point mutants of isocitrate dehydrogenases 1 and 2 (IDH2) generate 2-hydroxyglutarate, which inhibits lysine demethylases and increases heterochromatin. Tumor cells expressing IDH mutants are sensitive to PARP inhibitors (PARPi), offering an opportunity to eliminate IDH-driven tumor cells in therapy. Expression of an oncogenic IDH1 mutant in cells leads to aberrant heterochromatin formation at DNA breaks and impairs DNA repair through homologous recombination (HR), providing a possible explanation for the PARPi sensitivity of IDH mutant cells. However, a recent study published in Molecular Cell shows that IDH mutant tumors do not display the genomic alterations associated with HR defects. Instead, IDH mutants induce heterochromatin-dependent DNA replication stress. Furthermore, PARP is activated by the replication stress induced by IDH mutants and required for suppressing the ensuing DNA damage, providing an alternative model to explain the susceptibility of IDH mutant cells to PARPis. This study presents a new example of oncogene-induced and heterochromatin-dependent replication stress, and a role of PARP in the response to the stress, extending the molecular basis for PARP-targeted therapy.
Topics: Humans; Poly(ADP-ribose) Polymerase Inhibitors; Heterochromatin; Mutation; DNA Damage; Neoplasms; Isocitrate Dehydrogenase
PubMed: 37433029
DOI: 10.1158/0008-5472.CAN-23-2015