Mécanismes et conséquences des mutations

L’identification des mutations à l’origine de maladies génétiques chez l’homme a pris ces dernières années un essor considérable. Il est devenu possible d’établir le spectre des mutations délétères pour une maladie génétique donnée, et des bases de données internationales sont aujourd’hui accessibles via le réseau Internet. Le diagnostic génotypique des maladies héréditaires occupe actuellement une place prépondérante en matière de conseil génétique et de diagnostic prénatal. La connaissance du type de mutation délétère et des mécanismes en cause est essentielle pour déterminer la stratégie de diagnostic moléculaire adaptée à chaque situation. Cet article a pour objectif de présenter les différents types de mutations responsables de maladies génétiques (substitutions nucléotidiques, délétions ou insertions de petite taille, mutations dynamiques, grands remaniements…) et de récapituler les connaissances actuelles concernant les mécanismes moléculaires à l’origine de ces mutations. Leurs conséquences sur l’expression du gène (transcription et maturation du transcrit) et sur la fonction de la protéine sont également abordées dans cet article.The identification of mutations leading to human genetic diseases has grown into an intensive research field during the last few years. Through novel DNA analysis progress, it is now possible to determine the mutational spectrum for a given genetic disease and international databases are now available online. Genetic diagnosis of hereditary diseases has become an essential tool in genetic counselling and prenatal diagnosis. The knowledge of the deleterious mutation type and the molecular associated mechanism is fundamental in order to devise the optimal molecular diagnosis strategy. This review aims to present the various mutation categories involved in genetic diseases (single base-pair substitutions, small deletions or insertions, dynamic mutations, gross DNA lesions…) and to summarize our current knowledge about the main molecular mechanisms responsible for these mutations. Their deleterious consequences on gene expression, including transcription and transcript maturation, and protein loss or gain of function are also discussed in this review

Molecular profiling of malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1, based on large-scale real-time RT-PCR

BACKGROUND: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a complex range of clinical symptoms. The hallmark of NF1 is the onset of heterogeneous (dermal or plexiform) benign neurofibromas. Plexiform neurofibromas can give rise to malignant peripheral nerve sheath tumors (MPNSTs), and the underlying molecular mechanisms are largely unknown. RESULTS: To obtain further insight into the molecular pathogenesis of MPNSTs, we used real-time quantitative RT-PCR to quantify the mRNA expression of 489 selected genes in MPNSTs, in comparison with plexiform neurofibromas. The expression of 28 (5.7%) of the 489 genes was significantly different between MPNSTs and plexiform neurofibromas; 16 genes were upregulated and 12 were downregulated in MPNSTs. The altered genes were mainly involved in cell proliferation (MKI67, TOP2A, CCNE2), senescence (TERT, TERC), apoptosis (BIRC5/Survivin, TP73) and extracellular matrix remodeling (MMP13, MMP9, TIMP4, ITGB4). More interestingly, other genes were involved in the Ras signaling pathway (RASSF2, HMMR/RHAMM) and the Hedgehog-Gli signaling pathway (DHH, PTCH2). Several of the down-regulated genes were Schwann cell-specific (L1CAM, MPZ, S100B, SOX10, ERBB3) or mast cell-specific (CMA1, TPSB), pointing to a depletion and/or dedifferentiation of Schwann cells and mast cells during malignant transformation of plexiform neurofibromas. CONCLUSION: These data suggest that a limited number of signaling pathways, and particularly the Hedgehog-Gli signaling pathway, may be involved in malignant transformation of plexiform neurofibromas. Some of the relevant genes or their products warrant further investigation as potential therapeutic targets in NF1

“ COV’COP ” allows to detect CNVs responsible for inherited diseases among amplicons sequencing data

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Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: Consequences for PI3K binding on Gab1

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Dual mTORC1/2 inhibition induces anti-proliferative effect in NF1-associated plexiform neurofibroma and malignant peripheral nerve sheath tumor cells

International audienceApproximately 30-50% of individuals with Neurofibromatosis type 1 develop benign peripheral nerve sheath tumors, called plexiform neurofibromas (PNFs). PNFs can undergo malignant transformation to highly metastatic malignant peripheral nerve sheath tumors (MPNSTs) in 5-10% of NF1 patients, with poor prognosis. No effective systemic therapy is currently available for unresectable tumors. In tumors, the NF1 gene deficiency leads to Ras hyperactivation causing the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and inducing multiple cellular responses including cell proliferation. In this study, three NF1-null MPNST-derived cell lines (90-8, 88-14 and 96-2), STS26T sporadic MPNST cell line and PNF-derived primary Schwann cells were used to test responses to AZD8055, an ATP-competitive "active-site" mTOR inhibitor. In contrast to rapamycin treatment which only partially affected mTORC1 signaling, AZD8055 induced a strong inhibition of mTORC1 and mTORC2 signaling in MPNST-derived cell lines and PNF-derived Schwann cells. AZD8055 induced full blockade of mTORC1 leading to an efficient decrease of global protein synthesis. A higher cytotoxic effect was observed with AZD8055 compared to rapamycin in the NF1-null MPNST-derived cell lines with IC50 ranging from 70 to 140 nM and antiproliferative effect was confirmed in PNF-derived Schwann cells. Cell migration was impaired by AZD8055 treatment and cell cycle analysis showed a G0/G1 arrest. Combined effects of AZD8055 and PD0325901 MEK inhibitor as well as BRD4 (BromoDomain-containing protein 4) inhibitors showed a synergistic antiproliferative effect. These data suggest that NF1-associated peripheral nerve sheath tumors are an ideal target for AZD8055 as a single molecule or in combined therapies