1,721,133 research outputs found
The medical genetics of dystrophinopathies: Molecular genetic diagnosis and its impact on clinical practice
No full textA large variety of mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophies, diseases affecting predominantly the striated muscles (skeletal and cardiac). Rare mutations also account for the allelic disorder isolated X-linked dilated cardiomyopathy. Dystrophin protein is encoded by a huge gene located on the X chromosome and the understanding of its complex genomic architecture has unraveled general key functions in gene expression regulation. Dystrophin also exists as a number of other tissue specific isoforms, some exclusively or predominantly expressed in the brain and/or in other tissues. Genotype definition of the dystrophin gene in patients with dystrophinopathies has taught us much about functionally important domains of the protein itself and has also provided insights regarding several regulatory mechanisms governing the gene expression profile. This review focuses on the current understanding of the dystrophin mutations heterogeneity, genotype-phenotype correlations, as well as interpretation of the functional significance of mutations that often require non routine genetic studies. It also explores the impact of genetic diagnosis on clinical definition and on the discovery of biomarkers and personalized therapies.Our aim is to offer an overview of the medical genetic approach on the dystrophin gene and dystrophinopathies with implications for clinical practice and therapeutic perspectives. © 2012 Elsevier B.V
In vivo study of an aberrant dystrophin exon inclusion in X-linked dilated cardiomyopathy
No full textWe previously identified a dystrophin intron 11 rearrangement in one family with X-linked dilated cardiomyopathy, causing incorporation of an aberrant exon in a tissue-specific manner. In this study we analyzed the role of different intron 11 genomic regions in the regulation of splicing by using mini-genes based approach, in C2C12 (skeletal muscle) myoblasts and myotubes, H9C2 cardiomyocytes, and HeLa cells. We show that inclusion of the aberrant exon is favored in H9C2 and differentiated C2C12 myotubes. These data suggest that the aberrant exon undergoes a differentiation-specific splicing. Unexpectedly, length of intron has a favorable effect in inclusion of the aberrant exon in the cardiac cells, suggesting that cardiac cells might be more prone to steric hindrance of trans-acting factors, involved in the inclusion of the aberrant exon. Furthermore, the cultured cell system used can serve as a suitable model to study human alternative splicing
Progress in understanding GJB2-linked deafness
No full textMutations in the GJB2 gene (encoding for Connexin 26 protein) represent a leading cause of genetic hearing impairment. Extensive epidemiological and molecular studies have been reported, describing GJB2 mutations type, frequency and distribution. Moreover, several aspects of GJB2 mutations pathogenic effects have been elucidated taking advantage of in vitro and in vivo experimental approaches. Progress through reported studies is reviewed, highlighting recent major achievements in this field. Attention is focused on different unresolved questions regarding GJB2 deafness pathogenesis and genotype-phenotype relationships. Clarification of these important clues will significantly increase our understanding of the molecular basis of hearing loss and will improve the effectiveness of diagnosis and counselling of this frequent disease
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
Huntington's disease‐like presentation in Spinocerebellar ataxia type 12
No full textNo abstract is available for this article
Uso di modelli di trasformazione virale nello studio dei geni oncosoppressori tramite trasferimento monocromosomico.
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Calpain 3 deficiency presenting as fibre type disproportion: Scientific correspondence
No full textCongenital fibre type disproportion (CFTD) is a histological abnormality characterized by small type 1 muscle fibres, normally sized type 2 fibres and absence of other pathological features [1]. Type 1 fibre hypotrophy is observed in various neuromuscular disorders; thus CFTD should refer only to cases of fibre type disproportion (FTD) having the clinical features of a congenital myopathy and when other neuromuscular conditions have been ruled out [1]. A 36 year-old man, the only son of non consanguineous parents, had a normal birth and early development. Family history was unremarkable. At age 4 he presented with difficulty in climbing stairs and serum creatine kinase (CK) was twice the normal value. On clinical examination proximal limb and spine flexor muscles were weak whereas facial and neck muscles were spared. Shortening of the Achilles tendon was observed. A biopsy of the left vastus lateralis muscle showed FTD
NMD CHIP: Un Progetto Europeo per la diagnosi delle patologie neuromuscolari
No full textLe malattie neuromuscolari sono un ampio gruppo di patologie ereditarie caratterizzate da eterogeneità genetica e allelica. La
diagnosi molecolare è talora un processo lungo e dispendioso e nel 50% circa dei pazienti non si arriva ad identificare la
mutazione patologica. E’ dunque necessario sviluppare nuove tecniche che permettano ridurre sia tempi e costi delle indagini
sia il numero di pazienti “orfani” di mutazione e dunque privati della possibilità di essere inclusi in trials terapeutici innovativi.
NMD-Chip è un progetto europeo di cui l’Università di Ferrara è partner che ha come scopo quello di studiare i pazienti con
malattie neuromuscolari mediante specifici arrays genomici. Nell’ambito del progetto è stato creato ad oggi un array con 50
geni noti causare malattie neuromuscolari e uno con 40 geni noti causare neuropatie ereditarie. Abbiamo validato l’array per le
malattie neuromuscolari con DNA di pazienti affetti da distrofia di Duchenne identificando la mutazione patologica; abbiamo
inoltre studiato un gruppo di pazienti con miopatia miofibrillare risultati negativi alla analisi molecolare.Il progetto NMD Chip
prevede inoltre che i pazienti risultati negativi per i geni noti vengano studiati con array specifici per geni candidati. Inoltre lo
step finale è lo sviluppo di arrays per la identificazione di piccole mutazioni in tutti i geni indagati. La sensibilità e specificità
diagnostica di questo approccio nei pazienti sarà del 98% e permetterà di ridurre i tempi e i costi delle indagini nelle patologie
neuromuscolari
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