Опубликована: Янв. 1, 2024
Язык: Английский
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown
Опубликована: Янв. 3, 2025
The heart employs a specialized ribosome in its muscle cells to translate genetic information into proteins, fundamental adaptation with an elusive physiological role. Its significance is underscored by the discovery of neonatal patients suffering from often fatal failure caused rare compound heterozygous variants RPL3L, muscle-specific ribosomal protein that replaces ubiquitous RPL3 cardiac ribosomes.
Язык: Английский
Процитировано
0
medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown
Опубликована: Янв. 10, 2025
Abstract We report a family affected with childhood onset distal muscle weakness heterozygous chromosome 9q34 deletion encompassing the SPTAN1 gene. The was detected through exome-sequencing based copy number variant detection, segregates in four patients and is non-penetrant two other relatives. Electromyography, MRI biopsy revealed myopathic disease phenotype. Cellular consequences of were investigated using qPCR western blotting on patient-derived fibroblasts, which reduction RNA but not protein levels. Immunocytochemistry performed tissue did reveal α-II-spectrin. loss-of-function variants have previously been reported to cause hereditary motor neuropathy recently myopathy. Here, we confirm role haploinsufficiency as propose an age-dependent lack α-II-spectrin suggest CNV detection repurposed exome sequencing important diagnostic tool.
Язык: Английский
Процитировано
0
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown
Опубликована: Янв. 19, 2025
SUMMARY Arming T cells with a synthetically orthogonal IL-9 receptor (o9R) permits facile engraftment and potent anti-tumor functions. We considered whether the paucity of natural IL-9R expression could be exploited for cell immunotherapy given that, in mice, high doses were well-tolerated without discernible immune modulation. Compared to o9R, engineered exhibit superior tissue infiltration, stemness, activity. These qualities are consistent stronger JAK/STAT signal, which addition STAT1/3/5, unexpectedly includes STAT4 (canonically associated IL-12 but not common γ-chain cytokines). exquisitely sensitive perturbations proximal signaling, including structure-guided attenuation, amplification, rebalancing signals. Biased mutants uncover STAT1 as rheostat between proliferative stem-like terminally differentiated effector states. In summary, we identify native IL-9/IL-9R cytokine-receptor pair near-orthogonal an optimal signaling profile therapy.
Язык: Английский
Процитировано
0
Elsevier eBooks, Год журнала: 2025, Номер unknown
Опубликована: Янв. 1, 2025
Язык: Английский
Процитировано
0
Human Reproduction Update, Год журнала: 2025, Номер unknown
Опубликована: Янв. 3, 2025
mRNA splicing is a fundamental process in the reproductive system, playing pivotal role development and endocrine function, ensuring proper execution of meiosis, mitosis, gamete function. Trans-acting factors cis-acting elements are key players whose dysfunction can potentially lead to male female infertility. Although hundreds trans-acting have been implicated splicing, mechanisms by which these influence processes fully understood for only subset. Furthermore, clinical impact variations on human infertility has not comprehensively characterized, leading probable omissions pathogenic variants standard genetic analyses. This review aimed summarize our current understanding involved regulation their association with disorders. We introduced methods prioritizing functionally validating associated Additionally, we explored corresponding abnormal therapies that could provide insight into treating Systematic literature searches model organisms were performed PubMed database between May 1977 July 2024. To identify splicing-related genes infertility, search terms 'splice', 'splicing', 'variant', 'mutation' combined azoospermia, oligozoospermia, asthenozoospermia, multiple morphological abnormalities sperm flagella, acephalic spermatozoa, disorders sex development, early embryonic arrest, disorders, oocyte maturation premature ovarian failure, primary insufficiency, zona pellucida, fertilization defects, infertile, fertile, fertility, reproduction, reproductive. Our identified 5014 publications, 291 included final analysis. provided comprehensive overview biological focus roles elements. highlighted disruption 52 proteins spliceosome assembly catalytic activity recognized regulatory regions epigenetic The 73 validated 54 reported 20 types infertility; 27 them located outside canonical splice sites overlooked analysis due likely benign or uncertain significance. silico prediction prioritize potential may be true mechanisms. also strategies functional validation therapy approaches other diseases, providing reference reproduction treatment. will further promote more thorough processes, improved variant identification treatments N/A.
Язык: Английский
Процитировано
0
Frontiers in Pharmacology, Год журнала: 2025, Номер 16
Опубликована: Март 3, 2025
The recent advancement of sequencing technologies marks a significant shift in the character and complexity digital genomic data universe, encompassing diverse types molecular data, screened through manifold technological platforms. As result, plethora fully assembled genomes are generated that span vertically evolutionary scale. Notwithstanding tsunami thriving innovations accomplish unprecedented, nucleotide-level, structural functional annotation, an exhaustive, systemic, massive genome-wide annotation remains elusive, particularly when criterion is automation efficiency data-agnostic interpretation. latter paramount importance for elaboration strategies sophisticated, data-driven which aim to impart sustainable comprehensive systemic approach addressing whole genome variation. Therefore, it essential develop methods tools promote systematic with emphasis on mechanistic information exceeding limits coding regions, exploiting chunks pertinent residing non-coding including promoter enhancer sequences, RNAs, DNA methylation sites, transcription factor binding transposable elements more. This review provides overview current state-of-the-art genetic variation, existing bioinformatic tools, resources, databases platforms currently available or reported literature. Particular placed variants lie outside protein-coding regions (intronic intergenic), their potential co-localization regulatory element areas, such as putative RNA assessment impact investigated phenotype. In addition, leverage obtained from WGS GWAS-based analyses discussed, along future bioinformatics directions developments. These emphasize efficient, comprehensive, largely automated both variants, well optimal evaluation.
Язык: Английский
Процитировано
0
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown
Опубликована: Март 1, 2025
Abstract Missense mutations in PTPN11 , the gene encoding protein tyrosine phosphatase SHP2, are common several developmental disorders and cancers. While many SHP2 disrupt auto-inhibition cause hyperactivity, do not enhance catalytic activity. Both activating non-activating could potentially drive pathogenic signaling by altering protein-protein interactions or subcellular localization. We employed proximity-labeling proteomics to map interaction networks of wild-type ten clinically-relevant mutants, bound an inhibitor that stabilizes its auto-inhibited state. Our analyses revealed mutation-and inhibitor-dependent alterations interactome, with mutants also showing changes In particular, some had increased mitochondrial localization impacted function. This study provides a rich resource for exploring offers new insights into molecular basis SHP2-driven diseases. Furthermore, this work highlights capacity detect missense-mutation-dependent
Язык: Английский
Процитировано
0
American Journal of Ophthalmology, Год журнала: 2025, Номер unknown
Опубликована: Март 1, 2025
Язык: Английский
Процитировано
0
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown
Опубликована: Март 6, 2025
Variants of uncertain significance (VUS) limit the actionability genetic testing. A prominent example is MUTYH , a base excision repair factor associated with polyposis and colorectal cancer, which has pathogenic variant carrier rate approaching 1 in 50 individuals some populations. To systematically interrogate function we coupled deep mutational scanning DNA reporter containing its lesion substrate, 8OG:A. Our variant-to-function map covers >97% all possible point variants (n=10,941) achieves 100% accuracy classifying pathogenicity known clinical (n=247). Leveraging large registry, observe significant associations polyps more severely impaired missense conferring greater risk. We recapitulate functional differences between founder alleles, highlight sites complete intolerance, including residues that intercalate coordinate essential Zn 2+ or Fe-S clusters. This provides resource to resolve 1,032 existing VUS 90 conflicting interpretations demonstrates scalable strategy other clinically relevant factors.
Язык: Английский
Процитировано
0
medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown
Опубликована: Март 13, 2025
Atrial fibrillation (AF) is a common cardiac arrhythmia associated with an increased risk of stroke, heart failure, and death. Recent studies suggests that individuals early onset AF could be at developing failure dilated cardiomyopathy. This study aimed to identifying genetic variants in broad panel cardiomyopathy genes among early-onset individuals. We conducted targeted sequencing 29 cardiomyopathy-associated 478 below 45 years age from Danish cohort. Additionally, we analyzed whole exome data 374,289 the UK Biobank, including 29,108 AF. The cohort was stratified by diagnosis, pre-existing were excluded. focused on rare, truncating predicted lead loss function, potentially deleterious missense Biobank. In cohort, 42 (8.8%) had known genes. Biobank analysis showed inverse dose-response-like relationship between prevalence variants, ranging 3.8% <45 group 1.4% without diagnosis. rare similar pattern. identified high supports recent guideline suggestions indicates testing surveillance for relevant selected
Язык: Английский
Процитировано
0