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Indian Pediatrics Apr 2016Ghosal Type Hematodiaphyseal Dysplasia is an autosomal recessive disorder characterized by refractory anemia and diaphyseal bone dysplasia.
BACKGROUND
Ghosal Type Hematodiaphyseal Dysplasia is an autosomal recessive disorder characterized by refractory anemia and diaphyseal bone dysplasia.
CASE CHARACTERISTICS
A 3 y 9 mo-old male child presented with progressive anemia and bowing of thighs. Child was found to have a previously reported homozygous point mutation c.1238G>A, (p.Arg413Glu) in Exon 16 of TBXAS1 gene.
OUTCOME
Low dose steroid therapy resulted in normalization of hemoglobin and prevented further progression of bony changes.
MESSAGE
Refractory anemia in association with bony deformities should prompt pediatricians to investigate for inherited bony dysplasia.
Topics: Anemia, Refractory; Child, Preschool; Femur; Humans; Male; Osteochondrodysplasias; Point Mutation; Thromboxane-A Synthase
PubMed: 27156553
DOI: 10.1007/s13312-016-0851-y -
Journal of Bone and Mineral Research :... Oct 2017Mitochondrial dysfunction is associated with several clinical manifestations including diabetes mellitus (DM), neurological disorders, renal and hepatic diseases, and...
Mitochondrial dysfunction is associated with several clinical manifestations including diabetes mellitus (DM), neurological disorders, renal and hepatic diseases, and myopathy. Although mitochondrial dysfunction is associated with increased bone resorption and decreased bone formation in mouse models, effects of alterations in mitochondrial function on bone remodeling and mass have not been investigated in humans. We recruited 45 carriers (29 females, 16 males) with the m.3243A>G mutation and healthy controls matched for gender, age, height, and menopausal status. DXA and HRpQCT scans were performed, and bone turnover markers (BTMs) P1NP and CTX were measured. Cases and controls were well matched except for body weight, which was lower in cases (63.6 ± 18.1 kg versus 74.6 ± 14.8 kg, p < 0.01), and manifest DM was present in 25 of 45 cases (none in controls). Bone scans showed lower BMD at the lumbar spine, total hip, and femoral neck in cases. Mean lumbar spine, total hip, and femoral neck T-scores were -1.5, -1.3, and -1.6 in cases, respectively, and -0.8, -0.3, and -0.7 in controls (all p < 0.05). The m.3243A>G mutation was associated with lower BMD, cortical but not trabecular density, cortical thickness, and estimated bone strength. Furthermore, BTMs were lower in the m.3243A>G group before but not after adjustment for DM. The mitochondrial point mutation m.3243A>G was associated with decreased bone mass and strength. Although the coexistence of DM may have influenced bone turnover, the bone phenotype observed in m.3243A>G cases appeared to mirror age-related deterioration in bone, suggesting that mitochondrial dysfunction may cause a premature aging of bone. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
Topics: Absorptiometry, Photon; Biomarkers; Biomechanical Phenomena; Bone Density; Bone Remodeling; Case-Control Studies; Cortical Bone; Diabetes Mellitus; Female; Humans; Male; Middle Aged; Mitochondria; Point Mutation; Tomography, X-Ray Computed
PubMed: 28603900
DOI: 10.1002/jbmr.3193 -
Nucleic Acids Research Jul 2023Understanding the effects of mutations on protein stability is crucial for variant interpretation and prioritisation, protein engineering, and biotechnology. Despite...
Understanding the effects of mutations on protein stability is crucial for variant interpretation and prioritisation, protein engineering, and biotechnology. Despite significant efforts, community assessments of predictive tools have highlighted ongoing limitations, including computational time, low predictive power, and biased predictions towards destabilising mutations. To fill this gap, we developed DDMut, a fast and accurate siamese network to predict changes in Gibbs Free Energy upon single and multiple point mutations, leveraging both forward and hypothetical reverse mutations to account for model anti-symmetry. Deep learning models were built by integrating graph-based representations of the localised 3D environment, with convolutional layers and transformer encoders. This combination better captured the distance patterns between atoms by extracting both short-range and long-range interactions. DDMut achieved Pearson's correlations of up to 0.70 (RMSE: 1.37 kcal/mol) on single point mutations, and 0.70 (RMSE: 1.84 kcal/mol) on double/triple mutants, outperforming most available methods across non-redundant blind test sets. Importantly, DDMut was highly scalable and demonstrated anti-symmetric performance on both destabilising and stabilising mutations. We believe DDMut will be a useful platform to better understand the functional consequences of mutations, and guide rational protein engineering. DDMut is freely available as a web server and API at https://biosig.lab.uq.edu.au/ddmut.
Topics: Deep Learning; Mutation; Point Mutation; Protein Stability; Software; Proteins
PubMed: 37283042
DOI: 10.1093/nar/gkad472 -
Nature Chemical Biology Jan 2022Glutathione peroxidase 4 (GPX4), as the only enzyme in mammals capable of reducing esterified phospholipid hydroperoxides within a cellular context, protects cells from...
Glutathione peroxidase 4 (GPX4), as the only enzyme in mammals capable of reducing esterified phospholipid hydroperoxides within a cellular context, protects cells from ferroptosis. We identified a homozygous point mutation in the GPX4 gene, resulting in an R152H coding mutation, in three patients with Sedaghatian-type spondylometaphyseal dysplasia. Using structure-based analyses and cell models, including patient fibroblasts, of this variant, we found that the missense variant destabilized a critical loop, which disrupted the active site and caused a substantial loss of enzymatic function. We also found that the R152H variant of GPX4 is less susceptible to degradation, revealing the degradation mechanism of the GPX4 protein. Proof-of-concept therapeutic treatments, which overcome the impaired R152H GPX4 activity, including selenium supplementation, selective antioxidants and a deuterated polyunsaturated fatty acid were identified. In addition to revealing a general approach to investigating rare genetic diseases, we demonstrate the biochemical foundations of therapeutic strategies targeting GPX4.
Topics: Humans; Phospholipid Hydroperoxide Glutathione Peroxidase; Point Mutation; Precision Medicine; Proof of Concept Study
PubMed: 34931062
DOI: 10.1038/s41589-021-00915-2 -
Bioinformatics (Oxford, England) Jun 2020Next-generation sequencing technologies have accelerated the discovery of single nucleotide variants in the human genome, stimulating the development of predictors for...
MOTIVATION
Next-generation sequencing technologies have accelerated the discovery of single nucleotide variants in the human genome, stimulating the development of predictors for classifying which of these variants are likely functional in disease, and which neutral. Recently, we proposed CScape, a method for discriminating between cancer driver mutations and presumed benign variants. For the neutral class, this method relied on benign germline variants found in the 1000 Genomes Project database. Discrimination could, therefore, be influenced by the distinction of germline versus somatic, rather than neutral versus disease driver. This motivates this article in which we consider predictive discrimination between recurrent and rare somatic single point mutations based solely on using cancer data, and the distinction between these two somatic classes and germline single point mutations.
RESULTS
For somatic point mutations in coding and non-coding regions of the genome, we propose CScape-somatic, an integrative classifier for predictively discriminating between recurrent and rare variants in the human cancer genome. In this study, we use purely cancer genome data and investigate the distinction between minimal occurrence and significantly recurrent somatic single point mutations in the human cancer genome. We show that this type of predictive distinction can give novel insight, and may deliver more meaningful prediction in both coding and non-coding regions of the cancer genome. Tested on somatic mutations, CScape-somatic outperforms alternative methods, reaching 74% balanced accuracy in coding regions and 69% in non-coding regions, whereas even higher accuracy may be achieved using thresholds to isolate high-confidence predictions.
AVAILABILITY AND IMPLEMENTATION
Predictions and software are available at http://CScape-somatic.biocompute.org.uk/.
CONTACT
[email protected] or [email protected].
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Genome, Human; Genomics; Humans; Mutation; Neoplasms; Point Mutation; Software
PubMed: 32282885
DOI: 10.1093/bioinformatics/btaa242 -
Aging Jun 2021
Topics: Extracellular Vesicles; Gastrointestinal Microbiome; Gene Editing; Humans; Molecular Targeted Therapy; Point Mutation; Progeria
PubMed: 34176790
DOI: 10.18632/aging.203254 -
Cellular and Molecular Neurobiology Oct 2023The BAF (BRG1/BRM-associated factor) chromatin remodelling complex is essential for the regulation of DNA accessibility and gene expression during neuronal...
The BAF (BRG1/BRM-associated factor) chromatin remodelling complex is essential for the regulation of DNA accessibility and gene expression during neuronal differentiation. Mutations of its core subunit SMARCB1 result in a broad spectrum of pathologies, including aggressive rhabdoid tumours or neurodevelopmental disorders. Other mouse models have addressed the influence of a homo- or heterozygous loss of Smarcb1, yet the impact of specific non-truncating mutations remains poorly understood. Here, we have established a new mouse model for the carboxy-terminal Smarcb1 c.1148del point mutation, which leads to the synthesis of elongated SMARCB1 proteins. We have investigated its impact on brain development in mice using magnetic resonance imaging, histology, and single-cell RNA sequencing. During adolescence, Smarcb1 mice demonstrated rather slow weight gain and frequently developed hydrocephalus including enlarged lateral ventricles. In embryonic and neonatal stages, mutant brains did not differ anatomically and histologically from wild-type controls. Single-cell RNA sequencing of brains from newborn mutant mice revealed that a complete brain including all cell types of a physiologic mouse brain is formed despite the SMARCB1 mutation. However, neuronal signalling appeared disturbed in newborn mice, since genes of the AP-1 transcription factor family and neurite outgrowth-related transcripts were downregulated. These findings support the important role of SMARCB1 in neurodevelopment and extend the knowledge of different Smarcb1 mutations and their associated phenotypes.
Topics: Animals; Mice; Hydrocephalus; Mutation; Point Mutation; Signal Transduction; Transcription Factor AP-1
PubMed: 37219662
DOI: 10.1007/s10571-023-01361-5 -
Methods in Molecular Biology (Clifton,... 2020Identification of somatic mutations in tumor tissue is challenged by both technical artifacts, diverse somatic mutational processes, and genetic heterogeneity in the...
Identification of somatic mutations in tumor tissue is challenged by both technical artifacts, diverse somatic mutational processes, and genetic heterogeneity in the tumors. Indeed, recent independent benchmark studies have revealed low concordance between different somatic mutation callers. Here, we describe Somatic Mutation calling method using a Random Forest (SMuRF), a portable ensemble method that combines the predictions and auxiliary features from individual mutation callers using supervised machine learning. SMuRF has improved prediction accuracy for both somatic point mutations (single nucleotide variants; SNVs) and small insertions/deletions (indels) in cancer genomes and exomes. Here, we describe the method and provide a tutorial on the installation and application of SMuRF.
Topics: Genome, Human; Genomics; Humans; INDEL Mutation; Mutation; Neoplasms; Point Mutation; Polymorphism, Single Nucleotide; Software; Supervised Machine Learning
PubMed: 32124310
DOI: 10.1007/978-1-0716-0327-7_3 -
Journal of Cell Science Apr 2022Coilin is a conserved protein essential for integrity of nuclear membrane-less inclusions called Cajal bodies. Here, we report an amino acid substitution (p.K496E) found...
Coilin is a conserved protein essential for integrity of nuclear membrane-less inclusions called Cajal bodies. Here, we report an amino acid substitution (p.K496E) found in a widely-used human EGFP-coilin construct that has a dominant-negative effect on Cajal body formation. We show that this coilin-K496E variant fails to rescue Cajal bodies in cells lacking endogenous coilin, whereas the wild-type construct restores Cajal bodies in mouse and human coilin-knockout cells. In cells containing endogenous coilin, both the wild-type and K496E variant proteins accumulate in Cajal bodies. However, high-level overexpression of coilin-K496E causes Cajal body disintegration. Thus, a mutation in the C-terminal region of human coilin can disrupt Cajal body assembly. Caution should be used when interpreting data from coilin plasmids that are derived from this variant (currently deposited at Addgene).
Topics: Animals; Coiled Bodies; HeLa Cells; Humans; Mice; Mutation; Nuclear Proteins; Point Mutation
PubMed: 35356988
DOI: 10.1242/jcs.259587 -
Applied Microbiology and Biotechnology Feb 2024Metabolic engineering frequently makes use of point mutation and saturation mutation library creation. At present, sequencing is the only reliable and direct technique...
Metabolic engineering frequently makes use of point mutation and saturation mutation library creation. At present, sequencing is the only reliable and direct technique to detect point mutation and screen saturation mutation library. In this study, mismatch amplification mutation assay (MAMA) PCR was used to detect point mutation and screen saturation mutation library. In order to fine-tune the expression of odhA encoding 2-oxoglutarate dehydrogenase E1 component, a saturating mutant library of the RBS of odhA was created in Corynebacterium glutamicum P12 based on the CRISPR-Cas2a genome editing system, which increased the L-proline production by 81.3%. MAMA PCR was used to filter out 42% of the non-mutant transformants in the mutant library, which effectively reduced the workload of the subsequent fermentation test and the number of sequenced samples. The rapid and sensitive MAMA-PCR method established in this study provides a general strategy for detecting point mutations and improving the efficiency of mutation library screening. KEY POINTS: • MAMA PCR was optimized and developed to detect point mutation. • MAMA PCR greatly improves the screening efficiency of point mutation. • Attenuation of odhA expression in P12 effectively improves proline production.
Topics: Point Mutation; Mutation; Base Sequence; Corynebacterium glutamicum; Polymerase Chain Reaction
PubMed: 38305911
DOI: 10.1007/s00253-024-13036-2