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1.
Rheumatology (Oxford) ; 63(10): 2897-2902, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-38552317

RESUMEN

OBJECTIVE: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a complex immune disorder consequence of somatic UBA1 variants. Most reported pathogenic UBA1 variants are missense or splice site mutations directly impairing the translational start site at p.Met41, with recent studies showing that these variants are frequent causes of recurrent inflammation in older individuals. Here we aimed to characterize a novel UBA1 variant found in two patients clinically presenting with VEXAS syndrome. METHODS: Patients' data were collected from direct assessments and from their medical charts. Genomics analyses were undertaken by both Sanger and amplicon-based deep sequencing, and mRNA studies were undertaken by both cDNA subcloning and mRNA sequencing. RESULTS: We report a novel, somatic variant in a canonical splice site of the UBA1 gene (c.346-2A>G), which was identified in two unrelated adult male patients with late-onset, unexplained inflammatory manifestations including recurrent fever, Sweet syndrome-like neutrophilic dermatosis, and lung inflammation responsive only to glucocorticoids. RNA analysis of the patients' samples indicated aberrant mRNA splicing leading to multiple in-frame transcripts, including a transcript retaining the full sequence of intron 4 and a different transcript with the deletion of the first 15 nucleotides of exon 5. CONCLUSION: Here we describe abnormal UBA1 transcription as a consequence of the novel c.346-2A>G variant, identified in two patients with clinical features compatible with VEXAS syndrome. Overall, these results further demonstrate the expanding spectrum of variants in UBA1 leading to pathology and provide support for a complete gene evaluation in those patients considered candidates for VEXAS syndrome.


Asunto(s)
Sitios de Empalme de ARN , Enzimas Activadoras de Ubiquitina , Humanos , Masculino , Enzimas Activadoras de Ubiquitina/genética , Sitios de Empalme de ARN/genética , Persona de Mediana Edad , Enfermedades Autoinflamatorias Hereditarias/genética , Anciano , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Síndrome , Mutación , Adulto
2.
Front Immunol ; 15: 1381447, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38646532

RESUMEN

Undiagnosed monogenic diseases represent a challenging group of human conditions highly suspicious to have a genetic origin, but without conclusive evidences about it. We identified two brothers born prematurely from a non-consanguineous healthy couple, with a neonatal-onset, chronic disease characterized by severe skin and bone inflammatory manifestations and a fatal outcome in infancy. We conducted DNA and mRNA analyses in the patients' healthy relatives to identify the genetic cause of the patients' disease. DNA analyses were performed by both Sanger and next-generation sequencing, which identified two novel heterozygous IL1RN variants: the intronic c.318 + 2T>G variant in the father and a ≈2,600-bp intragenic deletion in the mother. IL1RN mRNA production was markedly decreased in both progenitors when compared with healthy subjects. The mRNA sequencing performed in each parent identified two novel, truncated IL1RN transcripts. Additional experiments revealed a perfect intrafamilial phenotype-genotype segregation following an autosomal recessive inheritance pattern. The evidences shown here supported for the presence of two novel loss-of-function (LoF) IL1RN pathogenic variants in the analyzed family. Biallelic LoF variants at the IL1RN gene cause the deficiency of interleukin-1 receptor antagonist (DIRA), a monogenic autoinflammatory disease with marked similarities with the patients described here. Despite the non-availability of the patients' samples representing the main limitation of this study, the collected evidences strongly suggest that the patients described here suffered from a lethal form of DIRA likely due to a compound heterozygous genotype at IL1RN, thus providing a reliable genetic diagnosis based on the integration of old medical information with currently obtained genetic data.


Asunto(s)
Heterocigoto , Proteína Antagonista del Receptor de Interleucina 1 , Mutación , Linaje , Femenino , Humanos , Recién Nacido , Masculino , Resultado Fatal , Enfermedades Autoinflamatorias Hereditarias/genética , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Proteína Antagonista del Receptor de Interleucina 1/genética , Fenotipo
3.
Forensic Sci Int Genet ; 57: 102646, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34875492

RESUMEN

We have genotyped the 58 STRs (27 autosomal, 24 Y-STRs and 7 X-STRs) and 94 autosomal SNPs in Illumina ForenSeq™ Primer Mix A in a sample of 248 men and 143 women from El Salvador, Central America. Regional division (Centro, Oriente, Occidente) showed in almost all cases FST values not significantly different from 0, and further analyses were applied only to the undivided, country-wide population. The overall random match probability (RMP) decreased from 6.79 × 10-31 in length-based genotypes in the 27 autosomal STRs to 1.47 × 10-34 in repeat-sequence based genotypes. Combining the autosomal loci in this set, RMP reaches 2.97 × 10-70. In a population genetic analysis, El Salvador showed the lowest FST values with US Hispanics both for autosomal and X-STRs; however, it was much closer to Native Americans for the latter than for the former, in accordance with the well-known gender-biased admixture that created most Latin American populations.


Asunto(s)
Dermatoglifia del ADN , Polimorfismo de Nucleótido Simple , El Salvador , Femenino , Frecuencia de los Genes , Genética de Población , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Repeticiones de Microsatélite
4.
Food Res Int ; 156: 111342, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35651089

RESUMEN

Antibiotic resistance genes (ARGs) have been identified in viral DNA isolated from different kinds of food, but little is known about their origin. In this study, twenty-one viromes were analyzed from samples of food previously reported to carry ARGs, including meat (poultry, veal, and pork), fish (Mediterranean, Atlantic, frozen, farmed and shellfish) and vegetables (lettuce, cucumber, and spinach). Classification of the contigs by Kraken revealed a large percentage of unclassified contigs (43.7-98.2%) in all the viromes. Only 0.05-7.1% of the contigs were identified as viral and of these, more than 91% belonged to different bacteriophage families, Podophages and Siphophages being the most prevalent. According to VirSorter, the largest number of viral contigs were derived from viromes of shellfish, followed by spinach. Spinach viromes also included the largest number of phage sequences identified by PHASTER. The abundant presence of bacterial genes in the viromes, including 16S rRNA genes, was attributed to the phage packaging of the bacterial genome fragments, as no bacterial DNA was found outside the viral capsids. The detection of 16S rRNA genes in the different viromes allowed diverse phage bacterial hosts to be identified. The three major functional groups of genes determined were related to metabolism, detoxification/resistance, and above all, biosynthesis. Various ARGs were quantified in the viromes by qPCR, the most prevalent being ß-lactamases, particularly blaTEM. Analysis of ARG diversity in the viromes by Prokka and CARD revealed various resistance-related genes, whereas a more restrictive search by ResFinder identified blaTEM in all the food viromes, blaOXA in Atlantic fish-1 and spinach-2, oqxB in lettuce-1, and dfr in spinach-2. The presence of ARGs in the food viromes points to bacterial DNA mobilization by transduction mechanisms. Transduction of resistances by phage particles may therefore contribute to the emergence of resistant strains along the food chain and should be monitored.


Asunto(s)
Bacteriófagos , Genes Bacterianos , Animales , Antibacterianos , Bacteriófagos/genética , Bovinos , ADN Bacteriano , Genes Bacterianos/genética , Prevalencia , ARN Ribosómico 16S/genética , Viroma
5.
Ann Clin Transl Neurol ; 9(12): 1985-1998, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36369764

RESUMEN

OBJECTIVES: Peripheral neuropathy is a relevant dose-limiting adverse event that can affect up to 90% of oncologic patients with colorectal cancer receiving oxaliplatin treatment. The severity of neurotoxicity often leads to dose reduction or even premature cessation of chemotherapy. Unfortunately, the limited knowledge about the molecular mechanisms related to oxaliplatin neurotoxicity leads to a lack of effective treatments to prevent the development of this clinical condition. In this context, the present work aimed to determine the exact molecular mechanisms involved in the development of oxaliplatin neurotoxicity in a murine model to try to find new therapeutical targets. METHODS: By single-cell RNA sequencing (scRNA-seq), we studied the transcriptomic profile of sensory neurons and satellite glial cells (SGC) of the Dorsal Root Ganglia (DRG) from a well-characterized mouse model of oxaliplatin neurotoxicity. RESULTS: Analysis of scRNA-seq data pointed to modulation of inflammatory processes in response to oxaliplatin treatment. In this line, we observed increased levels of NF-kB p65 protein, pro-inflammatory cytokines, and immune cell infiltration in DRGs and peripheral nerves of oxaliplatin-treated mice, which was accompanied by mechanical allodynia and decrease in sensory nerve amplitudes. INTERPRETATION: Our data show that, in addition to the well-described DNA damage, oxaliplatin neurotoxicity is related to an exacerbated pro-inflammatory response in DRG and peripheral nerves, and open new insights in the development of anti-inflammatory strategies as a treatment for preventing peripheral neuropathy induced by oxaliplatin.


Asunto(s)
Antineoplásicos , Síndromes de Neurotoxicidad , Enfermedades del Sistema Nervioso Periférico , Ratones , Animales , Oxaliplatino/toxicidad , Compuestos Organoplatinos/toxicidad , Antineoplásicos/toxicidad , Síndromes de Neurotoxicidad/etiología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Ganglios Espinales/metabolismo
6.
Front Genet ; 10: 1315, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31998370

RESUMEN

Sorting of individual chromosomes by Flow Cytometry (flow-sorting) is an enrichment method to potentially simplify genome assembly by isolating chromosomes from the context of the genome. We have recently developed a workflow to sequence native, unamplified DNA and applied it to the smallest human chromosome, the Y chromosome. Here, we modify improve upon that workflow to increase DNA recovery from chromosome sorting as well as sequencing yield. We apply it to sequence and assemble the largest human chromosome - chromosome 1 - of a Chinese individual using a single Oxford Nanopore MinION flow cell. We generate a selective and highly continuous assembly whose continuity reaches into the order of magnitude of the human reference GRCh38. We then use this assembly to call candidate structural variants against the reference and find 685 putative novel SV candidates. We propose this workflow as a potential solution to assemble structurally complex chromosomes, or the study of very large plant or animal genomes that might challenge traditional assembly strategies.

7.
Genome Biol Evol ; 10(6): 1584-1595, 2018 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-29901717

RESUMEN

Transposable elements (TEs) are a major driver of plant genome evolution. A part from being a rich source of new genes and regulatory sequences, TEs can also affect plant genome evolution by modifying genome size and shaping chromosome structure. TEs tend to concentrate in heterochromatic pericentromeric regions and their proliferation may expand these regions. Here, we show that after the split of melon and cucumber, TEs have expanded the pericentromeric regions of melon chromosomes that, probably as a consequence, show a very low recombination frequency. In contrast, TEs have not proliferated to a high extent in cucumber, which has small TE-dense pericentromeric regions and shows a relatively constant recombination rate along chromosomes. These differences in chromosome structure also translate in differences in gene nucleotide diversity. Although gene nucleotide diversity is essentially constant along cucumber chromosomes, melon chromosomes show a bimodal pattern of genetic variability, with a gene-poor region where variability is negatively correlated with gene density. Interestingly, genes are not homogeneously distributed in melon, and the high variable low-recombining pericentromeric regions show a higher concentration of melon-specific genes whereas genes shared with cucumber and other plants are essentially found in gene-rich chromosomal arms. The results presented here suggest that melon pericentromeric regions may allow gene sequences to evolve more freely than in other chromosomal compartments which may allow new ORFs to arise and eventually be selected. These results show that TEs can drastically change the structure of chromosomes creating different chromosomal compartments imposing different constraints for gene evolution.


Asunto(s)
Cucurbitaceae/genética , Elementos Transponibles de ADN/genética , Genoma de Planta/genética , Cromosomas de las Plantas/genética , Evolución Molecular , Variación Genética/genética , Tamaño del Genoma/genética
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