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Biomedical subjects

Dalil Hamroun

Publications and source records attributed to Dalil Hamroun.

5 recordsLinked to original sources
PubMed2007

Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy.

Approximately two-thirds of Duchenne muscular dystrophy (DMD) patients show intragenic deletions ranging from one to several exons of the DMD gene and leading to a premature stop codon. Other deletions that maintain the translational reading frame of the gene result in the milder Becker muscular dystrophy (BMD) form of the disease. Thus the opportunity to transform a DMD phenotype into a BMD phenotype appeared as a new treatment strategy with the development of antisense oligonucleotides technology, which is able to induce an exon skipping at the pre-mRNA level in order to restore an open reading frame. Because the DMD gene contains 79 exons, thousands of potential transcripts could be produced by exon skipping and should be investigated. The conventional approach considers skipping of a single exon. Here we report the comparison of single- and multiple-exon skipping strategies based on bioinformatic analysis. By using the Universal Mutation Database (UMD)-DMD, we predict that an optimal multiexon skipping leading to the del45-55 artificial dystrophin (c.6439_8217del) could transform the DMD phenotype into the asymptomatic or mild BMD phenotype. This multiple-exon skipping could theoretically rescue up to 63% of DMD patients with a deletion, while the optimal monoskipping of exon 51 would rescue only 16% of patients.

Adolescent↗
PubMed2006

Meta-analysis of the p53 mutation database for mutant p53 biological activity reveals a methodologic bias in mutation detection.

PURPOSE: Analyses of the pattern of p53 mutations have been essential for epidemiologic studies linking carcinogen exposure and cancer. We were concerned by the inclusion of dubious reports in the p53 databases that could lead to controversial analysis prejudicial to the scientific community. EXPERIMENTAL DESIGN: We used the universal mutation database p53 database (21,717 mutations) combined with a new p53 mutant activity database (2,300 mutants) to perform functional analysis of 1,992 publications reporting p53 alterations. This analysis was done using a statistical approach similar to that of clinical meta-analyses. RESULTS: This analysis reveals that some reports of infrequent mutations are associated with almost normal activities of p53 proteins. These particular mutations are frequently found in studies reporting multiple mutations in one tumor, silent mutations, or lacking mutation hotspots. These reports are often associated with particular methodologies, such as nested PCR, for which key controls are not satisfactory. CONCLUSIONS: We show the importance of accurate functional analysis before inferring any genetic variation. The quality of the p53 databases is essential in order to prevent erroneous analysis and/or conclusions. The availability of functional data from our new p53 web site (http://p53.free.fr and http://www.umd.be:2072/) will allow functional prescreening to identify potential artifactual data.

Databases, Factual↗
PubMed2006

The UMD TP53 database and website: update and revisions.

Mutation of the p53 gene is the most frequent genetic alteration found in human cancer, but it is also the most frequently reported with more than 22,000 mutations published in 2,000 papers. In 1991, we developed a database and software to handle and analyze all this information. The database has been widely used for clinical analysis and molecular epidemiology. We have expanded the scope of the database by integrating structural, phylogenetic and biological information on wild-type (wt) and mutant TP53. Integration of the TP53 mutant activity database provides unique information that will be useful to both clinicians and scientists. All of this information is available from a new website (www.umd.be:2072/) that will generate a detailed informative page for every TP53 mutant in the database. New tools to check TP53 mutations and minimize errors found in the literature are also available.

DNA Mutational Analysis↗
PubMed2005

UMD (Universal Mutation Database): 2005 update.

With the completion of the Human Genome Project, our vision of human genetic diseases has changed. The cloning of new disease-causing genes can now be performed in silico, and thousands of mutations are being identified in diagnostic and research laboratories yearly. Knowledge about these mutations and their association with clinical and biological data is essential for clinicians, geneticists, and researchers. To collect and analyze these data, we developed a generic software called Universal Mutation Databases (UMD) to create locus-specific databases. Here we report the new release (September 2004) of this freely available tool (www.umd.be), which allows the creation of LSDBs for virtually any gene and includes a large set of new analysis tools. We have implemented new features to integrate noncoding sequences, clinical data, pictures, monoclonal antibodies, and polymorphic markers (SNPs). Today the UMD retains all specifically designed tools to analyze mutations at the molecular level, as well as new sets of routines to search for genotype-phenotype correlations. We also created specific tools for infrequent mutations such as gross deletions and duplications, and deep intronic mutations. A large set of dedicated tools are now available for intronic mutations, including methods to calculate the consensus values (CVs) of potential splice sites and to search for exonic splicing enhancer (ESE) motifs. In addition, we have created specific routines to help researchers design new therapeutic strategies, such as exon skipping, aminoglycoside read-through of stop codons, or monoclonal antibody selection and epitope scanning for gene therapy.

Alternative Splicing↗