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Murviel-lès-Montpellier, France

Sabbagh A.,University of Paris Descartes | Pasmant E.,University of Paris Descartes | Imbard A.,Service de Biochimie Hormonologie | Luscan A.,University of Paris Descartes | And 10 more authors.
Human Mutation | Year: 2013

Neurofibromatosis type 1 (NF1) affects about one in 3,500 people in all ethnic groups. Most NF1 patients have private loss-of-function mutations scattered along the NF1 gene. Here, we present an original NF1 investigation strategy and report a comprehensive mutation analysis of 565 unrelated patients from the NF-France Network. A NF1 mutation was identified in 546 of the 565 patients, giving a mutation detection rate of 97%. The combined cDNA/DNA approach showed that a significant proportion of NF1 missense mutations (30%) were deleterious by affecting pre-mRNA splicing. Multiplex ligation-dependent probe amplification allowed the identification of restricted rearrangements that would have been missed if only sequencing or microsatellite analysis had been performed. In four unrelated families, we identified two distinct NF1 mutations within the same family. This fortuitous association points out the need to perform an exhaustive NF1 screening in the case of molecular discordant-related patients. A genotype-phenotype study was performed in patients harboring a truncating (N = 368), in-frame splicing (N = 36), or missense (N = 35) mutation. The association analysis of these mutation types with 12 common NF1 clinical features confirmed a weak contribution of the allelic heterogeneity of the NF1 mutation to the NF1 variable expressivity. © 2013 WILEY PERIODICALS, INC. Source


Dulic V.,Institute Of Genetique Moleculaire | Dulic V.,French National Center for Scientific Research | Dulic V.,Montpellier University
Methods in Molecular Biology | Year: 2013

The senescence program is activated in response to diverse stress stimuli potentially compromising genetic stability and leads to an irreversible cell cycle arrest. The mTOR pathway plays a crucial role in the regulation of cell metabolism and cellular growth. The goal of this chapter is to present evidence linking these two processes, which have one common regulator-the tumor suppressor p53. While the role of mTOR in senescence is still controversial, recent papers have shed new light onto this issue. This review, far from being exhaustive given the complexity of the field, will hopefully stimulate further research in this domain, whose relevance for ageing is becoming increasingly documented. © Springer Science+Business Media New York 2013. Source


Imbard A.,Service de Biochimie Hormonologie | Pasmant E.,University of Paris Descartes | Sabbagh A.,University of Paris Descartes | Luscan A.,University of Paris Descartes | And 11 more authors.
Journal of Human Genetics | Year: 2015

Neurofibromatosis type 1 (NF1) is caused by dominant loss-of-function mutations of the tumor suppressor NF1 containing 57 constitutive coding exons. A huge number of different pathogenic NF1 alterations has been reported. The aim of the present study was to evaluate the usefulness of a multiplex ligation-dependent probe amplification (MLPA) approach in NF1 patients to detect single and multi-exon NF1 gene copy number variations. A genotype-phenotype correlation was then performed in NF1 patients carrying these types of genetic alterations. Among 565 NF1 index cases from the French NF1 cohort, single and multi-exon deletions/duplications screening identified NF1 partial deletions/duplications in 22 patients (∼4%) using MLPA analysis. Eight single exon deletions, 11 multiple exons deletions, 1 complex rearrangement and 2 duplications were identified. All results were confirmed using a custom array-CGH. MLPA and custom array-CGH allowed the identification of rearrangements that were missed by cDNA/DNA sequencing or microsatellite analysis. We then performed a targeted next-generation sequencing of NF1 that allowed confirmation of all 22 rearrangements. No clear genotype-phenotype correlations were found for the most clinically significant disease features of NF1 in patients with single and multi-exons NF1 gene copy number changes. © 2015 The Japan Society of Human Genetics. Source


Lundgaard G.L.,Purdue University | Lundgaard G.L.,Gilead Sciences | Daniels N.E.,Purdue University | Daniels N.E.,Dow AgroSciences | And 13 more authors.
Journal of Cellular Biochemistry | Year: 2011

Bridging integrator 1 (BIN1) is a nucleocytoplasmic adaptor protein with tumor suppressor properties. The protein interacts with and inhibits the c-MYC transcription factor through the BIN1 MYC-binding domain (MBD). However, in vitro colony formation assays have clearly demonstrated that the MBD is not essential for BIN1-mediated growth arrest. We hypothesized that BIN1 contains a MYC-independent effector domain (MID) for cancer suppression. Because a functionally unique domain frequently contains a distinct structure, the human full-length BIN1 protein was subjected to limited trypsin digestion and the digested peptides were analyzed with Edman sequencing and mass spectrometry. We identified a trypsin-resistant peptide that corresponds to amino acids 146-268 of BIN1. It encompassed part of the BAR region, a putative effector region of BIN1. Computational analysis predicted that the peptide is very likely to exhibit coiled-coil motifs, implying a potential role for this region in sustaining the BIN1 structure and function. Like MBD-deleted BIN1, the trypsin-resistant peptide of BIN1 was predominantly present in the cytoplasm and was sufficient to inhibit cancer growth, regardless of dysregulated c-MYC activity. Our results suggest that the coiled-coil BIN1 BAR peptide encodes a novel BIN1 MID domain, through which BIN1 acts as a MYC-independent cancer suppressor. Copyright © 2011 Wiley-Liss, Inc. Source


Wurth L.,University of Strasbourg | Wurth L.,Center for Genomic Regulation and | Gribling-Burrer A.-S.,University of Strasbourg | Verheggen C.,Institute Of Genetique Moleculaire | And 7 more authors.
Nucleic Acids Research | Year: 2014

Mammalian mRNAs are generated by complex and coordinated biogenesis pathways and acquire 5′-end m7G caps that play fundamental roles in processing and translation. Here we show that several selenoprotein mRNAs are not recognized efficiently by translation initiation factor eIF4E because they bear a hypermethylated cap. This cap modification is acquired via a 5′-end maturation pathway similar to that of the small nucle(ol)ar RNAs (sn- and snoRNAs). Our findings also establish that the trimethylguanosine synthase 1 (Tgs1) interacts with selenoprotein mRNAs for cap hypermethylation and that assembly chaperones and core proteins devoted to sn- and snoRNP maturation contribute to recruiting Tgs1 to selenoprotein mRNPs. We further demonstrate that the hypermethylated-capped selenoprotein mRNAs localize to the cytoplasm, are associated with polysomes and thus translated. Moreover, we found that the activity of Tgs1, but not of eIF4E, is required for the synthesis of the GPx1 selenoprotein in vivo. © 2014 The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research. Source

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