1,721,134 research outputs found
Molecular bases of phenotypic and clinical variability in Duchenne and Becker muscular dystrophy
Full text linkLe distrofinopatie sono un gruppo di malattie legate al cromosoma X in modalità recessiva, dovute a mutazioni nel gene DMD. La forma più severa, la distrofia muscolare di Duchenne (DMD), è causata da mutazioni troncanti, che provocano una completa assenza della proteina distrofina nel muscolo scheletrico e cardiaco. Al contrario, la forma allelica più mite, nota come distrofia muscolare di Becker (BMD), è causata da mutazioni che rispettano la cornice di lettura del gene, dando origine a distrofina quantitativamente e/o qualitativamente alterata. La DMD è una malattia devastante, caratterizzata da una progressiva degenerazione del tessuto muscolare, con deficit di forza e disabilità sin dall'infanzia. La storia naturale è caratterizzata da perdita della deambulazione autonoma attorno all'età di 10 - 15 anni, e da ridotta aspettativa di vita a causa di complicanze respiratorie e cardiache nei giovani adulti. I glucocorticoidi (GC) possono ritardare la progressione della malattia, ma una cura definitiva non è ancora disponibile. Fra i trattamenti molecolari innovativi più promettenti, annoveriamo gli oligonucleotidi antisenso (AON) che inducono l’“exon skipping” di specifici esoni nelle mutazioni “out-of-frame”, e i composti che inducono il “readthrough” dei codoni di stop prematuri. Vi è una rilevante variabilità nella severità e velocità di progressione del deficit di forza e della degenerazione del tessuto muscolare nella DMD, che non si spiega, se non in piccola parte, in base alle diverse mutazioni patogenetiche, dal momento che tutti i pazienti presentano una completa o quasi completa assenza di distrofina. Recentemente, il nostro gruppo e altri autori hanno descritto modificatori genetici della DMD, cioè polimorfismi di singolo nucleotide (SNP) associati a espressività più o meno severa del fenotipo DMD: lo SNP rs28357094 nel promotere del gene SPP1, codificante per la citochina osteopontina, e un aplotipo codificante nel gene LTBP4 (Transforming growth factor β-Binding Protein 4). Queste varianti modulano l’espressione (SPP1) o alterano la sequenza aminoacidica (LTBP4) delle rispettive proteine, entrambe le quali sono coinvolte in vie di segnale pro-infiammatorie e pro-fibrotiche. Questi geni sono stati identificati come modificatori candidati con approcci diversi (rispettivamente, studi di profili di espressione e mappatura genomica di un modello murino). Il primo obiettivo di questa tesi è stato di ottenere una validazione indipendente dell’associazione genetica dello SNP rs28357094 nel gene SPP1 e dell'aplotipo LTBP4 con l’età di perdita della deambulazione nella DMD. Questo risultato è stato conseguito utilizzando dati raccolti nel Duchenne Natural History Study del Cooperative International Neuromuscular Research Group (CINRG-DNHS), condotto su 340 pazienti DMD in 20 Centri in tutto il mondo. In questa coorte, l’allele minore G dello SNP rs28357094 era associato a un prolungamento della deambulazione di 2 anni nei partecipanti al CINRG-DNHS che erano stati trattati con GC (p < 0.05), ma a nessun effetto nei partecipanti non trattati. Ciò suggerisce che questo SNP potrebbe essere un biomarcatore farmacodinamico di risposta ai GC. L'aplotipo omozigote “IAAM” di LTBP4, invece, era associato a un prolungamento della deambulazione di 2 anni nei partecipanti di origine europea (p < 0.05), ma non nell'intera coorte multietnica CINRG-DNHS, evidenziando la rilevanza della stratificazione di popolazione negli studi sui modificatori genetici. Il secondo obiettivo è stato rivolto alla identificazione di eventuali associazioni fra specifiche mutazioni DMD e perdita della deambulazione nel CINRG-DNHS. [...
Genetic diagnosis as a tool for personalized treatment of Duchenne muscular dystrophy
Full text linkAccurate definition of genetic mutations causing Duchenne muscular dystrophy (DMD) has always been relevant in order to provide genetic counseling to patients and families, and helps to establish the prognosis in the case where the distinction between Duchenne, Becker, or intermediate muscular dystrophy is not obvious. As molecular treatments aimed at dystrophin restoration in DMD are increasingly available as commercialized drugs or within clinical trials, genetic diagnosis has become an indispensable tool in order to determine eligibility for these treatments. DMD patients in which multiplex ligation-dependent probe amplification (MLPA) or similar techniques show a deletion suitable to exon skipping of exons 44, 45, 51, or 53, may be currently treated with AONs targeting these exons, in the context of clinical trials, or, as is the case for exon 51 skipping in the United States, with the first commercialized drug (eteplirsen). Patients who test negative at MLPA, but in whom DMD gene sequencing shows a nonsense mutation, may be amenable for treatment with stop codon readthrough compounds such as ataluren. Novel molecular approaches such as CRISPR-Cas9 targeting of specific DMD mutations are still in the preclinical stages, but appear promising. In conclusion, an accurate genetic diagnosis represents the entrance into a new scenario of personalized medicine in DMD
The "Usual Suspects": Genes for Inflammation, Fibrosis, Regeneration, and Muscle Strength Modify Duchenne Muscular Dystrophy
Full text linkDuchenne muscular dystrophy (DMD), the most severe form of dystrophinopathy, is quite homogeneous with regards to its causative biochemical defect, i.e., complete dystrophin deficiency, but not so much with regards to its phenotype. For instance, muscle weakness progresses to the loss of independent ambulation at a variable age, starting from before 10 years, to even after 16 years (with glucocorticoid treatment). Identifying the bases of such variability is relevant for patient counseling, prognosis, stratification in trials, and identification of therapeutic targets. To date, variants in five loci have been associated with variability in human DMD sub-phenotypes: SPP1, LTBP4, CD40, ACTN3, and THBS1. Four of these genes (SPP1, LTBP4, CD40, and THBS1) are implicated in several interconnected molecular pathways regulating inflammatory response to muscle damage, regeneration, and fibrosis; while ACTN3 is known as the gene for speed, as it contains a common truncating polymorphism (18% of the general population), which reduces muscle power and sprint performance. Studies leading to the identification of these modifiers were mostly based on a candidate gene approach, hence the identification of modifiers in usual suspect pathways, which are already known to modify muscle in disease or health. Unbiased approaches that are based on genome mapping have so far been applied only initially, but they will probably represent the focus of future developments in this field, and will hopefully identify novel, unsuspected therapeutic targets. In this article, we summarize the state of the art of modifier loci of human dystrophin deficiency, and attempt to assess their relevance and implications on both clinical management and translational research
Dystrophinopathies
No full textDystrophinopathies are a group of genetic disorders mainly affecting skeletal and
cardiac muscle, caused by deficiency of the protein dystrophin at the sarcolemma of
muscle fibers. Dystrophin is encoded by the Duchenne muscular dystrophy gene (DMD),
linked to the Xp21 locus. Duchenne muscular dystrophy (DMD) is the severe form of
dystrophinopathy caused by a complete deficiency of dystrophin protein, affecting 1 in ~
4,000 newborn males and representing one of the most common lethal childhood
disorders. Becker muscular dystrophy (BMD) is the relatively milder condition caused by
the presence of a reduced and/or partially functional dystrophin protein, and its clinical
manifestations range from severe to mild. Disease manifestations are relatively rare in
DMD/BMD carriers. Dilated cardiomyopathy (DCM) and respiratory insufficiency are
the most frequent complications of dystrophinopathies. Mental retardation is found in a
small percentage of patients. To date, dystrophinopathies have no definitive cure, but
benefit from palliative pharmacological therapy with steroids, and multidisciplinary care
for prevention and management of complications. Experimental molecular and genetic
therapies are under development but their efficacy has yet to be proven
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Mitochondrial disorders of the nuclear genome
Full text linkBACKGROUND: Mitochondrial myopathies are regulated by two genomes: the nuclear DNA, and the mitochondrial DNA. While, so far, most studies have dealt with mitochondrial myopathies due to deletions or point mutations in the mitochondrial DNA, a new field of investigation is that of syndromes due to mutations in the nuclear DNA. These latter disorders have mendelian inheritance.
RESULTS: Three representative cases have been selected: one with COX deficiency and a Leigh syndrome due to a SURF1 gene mutation, one due to a defect of Coenzyme Q synthesis and one with dominant optic atrophy due to a mutation in the OPA1 gene.
CONCLUSIONS: Future developments will show that many neurodegenerative disorders are due to mutations of nuclear genes controlling mitochondrial function, fusion and fission
The complex landscape of DMD mutations: moving towards personalized medicine
No full text: Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by progressive muscle degeneration, with respiratory and cardiac complications, caused by mutations in the DMD gene, encoding the protein dystrophin. Various DMD mutations result in different phenotypes and disease severity. Understanding genotype/phenotype correlations is essential to optimize clinical care, as mutation-specific therapies and innovative therapeutic approaches are becoming available. Disease modifier genes, trans-active variants influencing disease severity and phenotypic expressivity, may modulate the response to therapy, and become new therapeutic targets. Uncovering more disease modifier genes via extensive genomic mapping studies offers the potential to fine-tune prognostic assessments for individuals with DMD. This review provides insights into genotype/phenotype correlations and the influence of modifier genes in DMD
Comunità planctoniche in bacini artificiali alpini in rapporto all’utilizzo antropico della risorsa acqua
No full textSono state analizzate le variazioni spazio-temporali delle comunità planctoniche in tre bacini artificiali dell'arco alpino (regionr trentino Alto Adige) in relazione all'uso della risorsa acqu
Compressed computations using wavelets for hidden Markov models with continuous observations
No full textCompression as an accelerant of computation is increasingly recognized as an important component in engineering fast real-world machine learning methods for big data; c.f., its impact on genome-scale approximate string matching. Previous work showed that compression can accelerate algorithms for Hidden Markov Models (HMM) with discrete observations, both for the classical frequentist HMM algorithms—Forward Filtering, Backward Smoothing and Viterbi—and Gibbs sampling for Bayesian HMM. For Bayesian HMM with continuous-valued observations, compression was shown to greatly accelerate computations for specific types of data. For instance, data from large-scale experiments interrogating structural genetic variation can be assumed to be piece-wise constant with noise, or, equivalently, data generated by HMM with dominant self-transition probabilities. Here we extend the compressive computation approach to the classical frequentist HMM algorithms on continuous-valued observations, providing the first compressive approach for this problem. In a large-scale simulation study, we demonstrate empirically that in many settings compressed HMM algorithms very clearly outperform the classical algorithms with no, or only an insignificant effect, on the computed probabilities and infered state paths of maximal likelihood. This provides an efficient approach to big data computations with HMM. An open-source implementation of the method is available from https://github.com/lucabello/wavelet-hmms
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