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Cancer Research Jun 2024DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that decrease 5'-cytosine methylation. DNMTi are used clinically based on the...
DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that decrease 5'-cytosine methylation. DNMTi are used clinically based on the hypothesis that cytosine demethylation will lead to re-expression of tumor suppressor genes. 5-Aza-4'-thio-2'-deoxycytidine (Aza TdCyd or ATC) is a recently described thiol substituted DNMTi that has been shown to have anti-tumor activity in solid tumor models. Here, we investigated the therapeutic potential of ATC in a murine transplantation model of myelodysplastic syndrome. ATC treatment led to transformation of transplanted wild-type bone marrow nucleated cells into lymphoid leukemia, and healthy mice treated with ATC also developed lymphoid leukemia. Whole exome sequencing revealed thousands of acquired mutations, almost all of which were C>G transversions in a specific 5'-NCG-3' context. These mutations involved dozens of genes involved in human lymphoid leukemia, such as Notch1, Pten, Pax5, Trp53, and Nf1. Human cells treated in vitro with ATC showed thousands of acquired C>G transversions in a similar context. Deletion of Dck, the rate-limiting enzyme for the cytidine salvage pathway, eliminated C>G transversions. Taken together, these findings demonstrate a highly penetrant mutagenic and leukemogenic phenotype associated with ATC.
PubMed: 38832931
DOI: 10.1158/0008-5472.CAN-23-2785 -
Human Molecular Genetics Jun 2024Spinocerebellar ataxia type 10 (SCA10) is a rare autosomal dominant ataxia caused by a large expansion of the (ATTCT)n repeat in ATXN10. SCA10 was described in Native...
Spinocerebellar ataxia type 10 (SCA10) is a rare autosomal dominant ataxia caused by a large expansion of the (ATTCT)n repeat in ATXN10. SCA10 was described in Native American and Asian individuals which prompted a search for an expanded haplotype to confirm a common ancestral origin for the expansion event. All patients with SCA10 expansions in our cohort share a single haplotype defined at the 5'-end by the minor allele of rs41524547, located ~35 kb upstream of the SCA10 expansion. Intriguingly, rs41524547 is located within the miRNA gene, MIR4762, within its DROSHA cleavage site and just outside the seed sequence for mir4792-5p. The world-wide frequency of rs41524547-G is less than 5% and found almost exclusively in the Americas and East Asia-a geographic distribution that mirrors reported SCA10 cases. We identified rs41524547-G(+) DNA from the 1000 Genomes/International Genome Sample Resource and our own general population samples and identified SCA10 repeat expansions in up to 25% of these samples. The reduced penetrance of these SCA10 expansions may be explained by a young (pre-onset) age at sample collection, a small repeat size, purity of repeat units, or the disruption of miR4762-5p function. We conclude that rs41524547-G is the most robust at-risk SNP allele for SCA10, is useful for screening of SCA10 expansions in population genetics studies and provides the most compelling evidence to date for a single, prehistoric origin of SCA10 expansions sometime prior to or during the migration of individuals across the Bering Land Bridge into the Americas.
PubMed: 38832639
DOI: 10.1093/hmg/ddae092 -
Disease Models & Mechanisms May 2024Recent progress in human disease genetics is leading to rapid advances in understanding pathobiological mechanisms. However, the sheer number of risk-conveying genetic... (Review)
Review
Recent progress in human disease genetics is leading to rapid advances in understanding pathobiological mechanisms. However, the sheer number of risk-conveying genetic variants being identified demands in vivo model systems that are amenable to functional analyses at scale. Here we provide a practical guide for using the diploid frog species Xenopus tropicalis to study many genes and variants to uncover conserved mechanisms of pathobiology relevant to human disease. We discuss key considerations in modelling human genetic disorders: genetic architecture, conservation, phenotyping strategy and rigour, as well as more complex topics, such as penetrance, expressivity, sex differences and current challenges in the field. As the patient-driven gene discovery field expands significantly, the cost-effective, rapid and higher throughput nature of Xenopus make it an essential member of the model organism armamentarium for understanding gene function in development and in relation to disease.
Topics: Animals; Xenopus; Humans; Disease Models, Animal; Genetic Diseases, Inborn; Phenotype
PubMed: 38832520
DOI: 10.1242/dmm.050754 -
MedRxiv : the Preprint Server For... May 2024Approximately 3% of the human genome consists of repetitive elements called tandem repeats (TRs), which include short tandem repeats (STRs) of 1-6bp motifs and variable...
Approximately 3% of the human genome consists of repetitive elements called tandem repeats (TRs), which include short tandem repeats (STRs) of 1-6bp motifs and variable number tandem repeats (VNTRs) of 7+bp motifs. TR variants contribute to several dozen mono- and polygenic diseases but remain understudied and "enigmatic," particularly relative to single nucleotide variants. It remains comparatively challenging to interpret the clinical significance of TR variants. Although existing resources provide portions of necessary data for interpretation at disease-associated loci, it is currently difficult or impossible to efficiently invoke the additional details critical to proper interpretation, such as motif pathogenicity, disease penetrance, and age of onset distributions. It is also often unclear how to apply population information to analyses. We present STRchive (S-T-archive, http://strchive.org/ ), a dynamic resource consolidating information on TR disease loci in humans from research literature, up-to-date clinical resources, and large-scale genomic databases, with the goal of streamlining TR variant interpretation at disease-associated loci. We apply STRchive -including pathogenic thresholds, motif classification, and clinical phenotypes-to a gnomAD cohort of ∼18.5k individuals genotyped at 60 disease-associated loci. Through detailed literature curation, we demonstrate that the majority of TR diseases affect children despite being thought of as adult diseases. Additionally, we show that pathogenic genotypes can be found within gnomAD which do not necessarily overlap with known disease prevalence, and leverage STRchive to interpret locus-specific findings therein. We apply a diagnostic blueprint empowered by STRchive to relevant clinical vignettes, highlighting possible pitfalls in TR variant interpretation. As a living resource, STRchive is maintained by experts, takes community contributions, and will evolve as understanding of TR diseases progresses.
PubMed: 38826469
DOI: 10.1101/2024.05.21.24307682 -
Bioorganic Chemistry Aug 2024There is a continuous and pressing need to establish new brain-penetrant bioactive compounds with anti-cancer properties. To this end, a new series of...
There is a continuous and pressing need to establish new brain-penetrant bioactive compounds with anti-cancer properties. To this end, a new series of 4'-((4-substituted-4,5-dihydro-1H-1,2,3-triazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile (OTBN-1,2,3-triazole) derivatives were synthesized by click chemistry. The series of bioactive compounds were designed and synthesized from diverse alkynes and N-OTBN, using copper (II) acetate monohydrate in aqueous dimethylformamide at room temperature. Besides being highly cost-effective and significantly reducing synthesis, the reaction yielded 91-98 % of the target products without the need of any additional steps or chromatographic techniques. Two analogues exhibit promising anti-cancer biological activities. Analogue 4l shows highly specific cytostatic activity against lung cancer cells, while analogue 4k exhibits pan-cancer anti-growth activity. A kinase screen suggests compound 4k has single-digit micromolar activity against kinase STK33. High STK33 RNA expression correlates strongly with poorer patient outcomes in both adult and pediatric glioma. Compound 4k potently inhibits cell proliferation, invasion, and 3D neurosphere formation in primary patient-derived glioma cell lines. The observed anti-cancer activity is enhanced in combination with specific clinically relevant small molecule inhibitors. Herein we establish a novel biochemical kinase inhibitory function for click-chemistry-derived OTBN-1,2,3-triazole analogues and further report their anti-cancer activity in vitro for the first time.
Topics: Humans; Triazoles; Click Chemistry; Antineoplastic Agents; Cell Proliferation; Structure-Activity Relationship; Drug Screening Assays, Antitumor; Protein Kinase Inhibitors; Molecular Structure; Protein Serine-Threonine Kinases; Dose-Response Relationship, Drug; Cell Line, Tumor; Nitriles
PubMed: 38824700
DOI: 10.1016/j.bioorg.2024.107485 -
Journal of Neuroimmunology Jul 2024Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare immune-mediated neuropathy for which there is no clearly identified risk factor. The present...
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare immune-mediated neuropathy for which there is no clearly identified risk factor. The present study identified rare variants in the FBXO38 gene in three familial cases of CIDP with response to corticosteroids in three generations with incomplete penetrance, and in an unrelated fourth case with diffuse nerve hypertrophy. FBXO38 may be involved in the regulation of the immunity mediated by CD8 T cells, which have an important role in CIDP pathophysiology, through PD1 degradation. Considering these findings, FBXO38 should be investigated as a potential genetic factor in larger cohorts of patients with CIDP.
Topics: Humans; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Male; Female; Middle Aged; F-Box Proteins; Adult; Pedigree; Aged
PubMed: 38823119
DOI: 10.1016/j.jneuroim.2024.578381 -
Journal of Parkinson's Disease 2024The penetrance of common genetic risk variants for Parkinson's disease (PD) is low. Pesticide exposure increases PD risk, but how exposure affects penetrance is not well...
BACKGROUND
The penetrance of common genetic risk variants for Parkinson's disease (PD) is low. Pesticide exposure increases PD risk, but how exposure affects penetrance is not well understood.
OBJECTIVE
To determine the relationship between occupational pesticide exposure and PD in people with LRRK2 and GBA risk variants.
METHODS
Participants of the Parkinson's Progression Markers Initiative (PPMI) with a LRRK2-G2019 S or GBA risk variant provided information about occupational pesticide exposure. We compared exposure in carriers with and without PD. Among carriers with PD, we used Cox proportional hazard models to compare time-to impairment in balance, cognition, and activities of daily living (ADLs) between participants with and without prior occupational pesticide exposure.
RESULTS
378 participants with a risk variant provided exposure information; 176 with LRRK2-G2019 S (54 with and 122 without PD) and 202 with GBA variants (47 with and 155 without PD). Twenty-six participants reported pesticide exposure. People with a GBA variant and occupational pesticide exposure had much higher odds of PD (aOR: 5.4, 95% CI 1.7-18.5, p < 0.01). People with a LRRK2 variant and a history of occupational pesticide exposure had non-significantly elevated odds of PD (aOR 1.3, 95% CI 0.4-4.6, p = 0.7). Among those with PD, pesticide exposure was associated with a higher risk of balance problems and cognitive impairment in LRRK2-PD and functional impairment in GBA-PD, although associations were not statistically significant.
CONCLUSIONS
Occupational pesticide exposure may increase penetrance of GBA-PD and may be associated with faster symptom progression. Further studies in larger cohorts are necessary.
Topics: Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Female; Parkinson Disease; Male; Glucosylceramidase; Occupational Exposure; Pesticides; Aged; Middle Aged; Penetrance; Activities of Daily Living; Cognitive Dysfunction
PubMed: 38820021
DOI: 10.3233/JPD-240015 -
Genetics in Medicine : Official Journal... May 2024
Consideration of disease penetrance in the selection of secondary findings gene-disease pairs: A policy statement of the American College of Medical Genetics and Genomics (ACMG).
PubMed: 38819344
DOI: 10.1016/j.gim.2024.101142 -
Biometrics Mar 2024We congratulate the authors for the new meta-analysis model that accounts for different outcomes. We discuss the modeling choice and the Bayesian setting, specifically,...
We congratulate the authors for the new meta-analysis model that accounts for different outcomes. We discuss the modeling choice and the Bayesian setting, specifically, we point out the connection between the Bayesian hierarchical model and a mixed-effect model formulation to subsequently discuss possible future method extensions.
Topics: Bayes Theorem; Humans; Meta-Analysis as Topic; Neoplasms; Penetrance; Models, Statistical; Risk Assessment
PubMed: 38819315
DOI: 10.1093/biomtc/ujae043 -
Biometrics Mar 2024The five discussions of our paper provide several modeling alternatives, extensions, and generalizations that can potentially guide future research in meta-analysis. In...
The five discussions of our paper provide several modeling alternatives, extensions, and generalizations that can potentially guide future research in meta-analysis. In this rejoinder, we briefly summarize and comment on some of those points.
Topics: Humans; Meta-Analysis as Topic; Penetrance; Neoplasms; Models, Statistical; Risk Assessment; Genetic Predisposition to Disease
PubMed: 38819314
DOI: 10.1093/biomtc/ujae040