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Cowling B.S.,Igbmc Institute Of Genetique Et Of Biologie Moleculaire Et Cellulaire | Cowling B.S.,Collège de France | Cottle D.L.,University of Cambridge | Wilding B.R.,Monash University | And 3 more authors.
Neuromuscular Disorders | Year: 2011

Mutations in the four and a half LIM protein 1 (FHL1) gene were recently identified as the cause of four distinct skeletal muscle diseases. Since the initial report outlining the first fhl1 mutation in 2008, over 25 different mutations have been identified in patients with reducing body myopathy, X-linked myopathy characterized by postural muscle atrophy, scapuloperoneal myopathy and Emery-Dreifuss muscular dystrophy. Reducing body myopathy was first described four decades ago, its underlying genetic cause was unknown until the discovery of fhl1 mutations. X-linked myopathy characterized by postural muscle atrophy is a novel disease where fhl1 mutations are the only cause. This review will profile each of the FHL1, with a comprehensive analysis of mutations, a comparison of the clinical and histopathological features and will present several hypotheses for the possible disease mechanism(s). © 2011 Elsevier B.V.


Martelli A.,Igbmc Institute Of Genetique Et Of Biologie Moleculaire Et Cellulaire | Martelli A.,French Institute of Health and Medical Research | Martelli A.,French National Center for Scientific Research | Martelli A.,University of Strasbourg | And 7 more authors.
DMM Disease Models and Mechanisms | Year: 2012

In 1996, a link was identified between Friedreich's ataxia (FRDA), the most common inherited ataxia in men, and alterations in the gene encoding frataxin (FXN). Initial studies revealed that the disease is caused by a unique, most frequently biallelic, expansion of the GAA sequence in intron 1 of FXN. Since the identification of this link, there has been tremendous progress in understanding frataxin function and the mechanism of FRDA pathology, as well as in developing diagnostics and therapeutic approaches for the disease. These advances were the subject of the 4th International Friedreich's Ataxia Conference held on 5th-7th May in the Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. More than 200 scientists gathered from all over the world to present the results of research spanning all areas of investigation into FRDA (including clinical aspects, FRDA pathogenesis, genetics and epigenetics of the disease, development of new models of FRDA, and drug discovery). This review provides an update on the understanding of frataxin function, developments of animal and cellular models of the disease, and recent advances in trying to uncover potential molecules for therapy. © 2012. Published by The Company of Biologists Ltd.


Hamiche A.,Igbmc Institute Of Genetique Et Of Biologie Moleculaire Et Cellulaire | Hamiche A.,French National Center for Scientific Research | Hamiche A.,French Institute of Health and Medical Research | Hamiche A.,University of Strasbourg | And 4 more authors.
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms | Year: 2012

Chromatin is a highly dynamic nucleoprotein structure, which orchestrates all nuclear process from DNA replication to DNA repair, from transcription to recombination. The proper in vivo assembly of nucleosome, the basic repeating unit of chromatin, requires the deposition of two H3-H4 dimer pairs followed by the addition of two dimers of H2A and H2B. Histone chaperones are responsible for delivery of histones to the site of chromatin assembly and histone deposition onto DNA, histone exchange and removal. Distinct factors have been found associated with different histone H3 variants, which facilitate their deposition. Unraveling the mechanism of histone deposition by specific chaperones is of key importance to epigenetic regulation. In this review, we focus on histone H3 variants and their deposition mechanisms. This article is part of a Special Issue entitled:Histone chaperones and Chromatin assembly. © 2011 Elsevier B.V.


Hnia K.,Igbmc Institute Of Genetique Et Of Biologie Moleculaire Et Cellulaire | Hnia K.,French Institute of Health and Medical Research | Hnia K.,French National Center for Scientific Research | Hnia K.,University of Strasbourg | And 8 more authors.
Trends in Molecular Medicine | Year: 2012

The myotubularin family of phosphoinositide phosphatases includes several members mutated in neuromuscular diseases or associated with metabolic syndrome, obesity, and cancer. Catalytically dead phosphatases regulate their active homologs by heterodimerization and potentially represent key players in the phosphatase-kinase balance. Although the enzymatic specificity for phosphoinositides indicates a role for myotubularins in endocytosis and membrane trafficking, recent findings in cellular and animal models suggest that myotubularins regulate additional processes including cell proliferation and differentiation, autophagy, cytokinesis, and cytoskeletal and cell junction dynamics. In this review, we discuss how myotubularins regulate such diverse processes, emphasizing newly identified functions in a physiological and pathological context. A better understanding of myotubularin pathophysiology will pave the way towards therapeutic strategies. © 2012 Elsevier Ltd.


Ces A.,Mouse Clinical Institute | Reiss D.,Igbmc Institute Of Genetique Et Of Biologie Moleculaire Et Cellulaire | Walter O.,Igbmc Institute Of Genetique Et Of Biologie Moleculaire Et Cellulaire | Walter O.,University of Strasbourg | And 6 more authors.
Neuropsychopharmacology | Year: 2012

Nociceptin/orphanin FQ (N/OFQ) peptide and its receptor (NOP receptor) have been implicated in a host of brain functions and diseases, but the contribution of this neuropeptide system to behavioral processes of relevance to psychosis has not been investigated. We examined the effect of the NOP receptor antagonists, Compound 24 and J-113397, and the synthetic agonist, Ro64-6198, on time function (2-2000 ms prepulse-pulse intervals) of acoustic (80 dB/10 ms prepulse) and visual (1000 Lux/20 ms prepulse) prepulse inhibition of startle reflex (PPI), a preattentive sensory filtering mechanism that is central to perceptual and mental integration. The effects of the dopamine D1-like receptor agonist, SKF-81297, the D2-like receptor agonist, quinelorane, and the mixed D1/D2 agonist, apomorphine, were studied for comparison. When acoustic stimulus was used as prepulse, BALB/cByJ mice displayed a monotonic time function of PPI, and consistent with previous studies, apomorphine and SKF-81279 induced PPI impairment, whereas quinelorane had no effect. None of the NOP receptor ligands was effective on acoustic PPI. When flash light was used as prepulse, BALB/cByJ mice displayed a bell-shaped time function of PPI and all dopamine agonists were active. Ro64-6198 was also effective in reducing visual PPI. NOP receptor antagonists showed no activity but blocked disruptive effect of Ro64-6198. Finally, coadministration of the typical antipsychotic, haloperidol, attenuated PPI impairment induced by Ro64-6198, revealing involvement of a dopaminergic component. These findings show that pharmacological stimulation of NOP or dopamine D2-like receptors is more potent in disrupting visual than acoustic PPI in mice, whereas D1-like receptor activation disrupts both. They further suggest that dysfunction of N/OFQ transmission may be implicated in the pathogenesis of psychotic manifestations. © 2012 American College of Neuropsychopharmacology. All rights reserved.


Vasli N.,Igbmc Institute Of Genetique Et Of Biologie Moleculaire Et Cellulaire | Vasli N.,French Institute of Health and Medical Research | Vasli N.,French National Center for Scientific Research | Vasli N.,University of Strasbourg | And 6 more authors.
Acta Neuropathologica | Year: 2013

Neuromuscular disorders (NMD) such as neuropathy or myopathy are rare and often severe inherited disorders, affecting muscle and/or nerves with neonatal, childhood or adulthood onset, with considerable burden for the patients, their families and public health systems. Genetic and clinical heterogeneity, unspecific clinical features, unidentified genes and the implication of large and/or several genes requiring complementary methods are the main drawbacks in routine molecular diagnosis, leading to increased turnaround time and delay in the molecular validation of the diagnosis. The application of massively parallel sequencing, also called next generation sequencing, as a routine diagnostic strategy could lead to a rapid screening and fast identification of mutations in rare genetic disorders like NMD. This review aims to summarize and to discuss recent advances in the genetic diagnosis of neuromuscular disorders, and more generally monogenic diseases, fostered by massively parallel sequencing. We remind the challenges and benefit of obtaining an accurate genetic diagnosis, introduce the massively parallel sequencing technology and its novel applications in diagnosis of patients, prenatal diagnosis and carrier detection, and discuss the limitations and necessary improvements. Massively parallel sequencing synergizes with clinical and pathological investigations into an integrated diagnosis approach. Clinicians and pathologists are crucial in patient selection and interpretation of data, and persons trained in data management and analysis need to be integrated to the diagnosis pipeline. Massively parallel sequencing for mutation identification is expected to greatly improve diagnosis, genetic counseling and patient management. © 2012 Springer-Verlag Berlin Heidelberg.


Beilschmidt L.K.,Igbmc Institute Of Genetique Et Of Biologie Moleculaire Et Cellulaire | Beilschmidt L.K.,French Institute of Health and Medical Research | Beilschmidt L.K.,French National Center for Scientific Research | Beilschmidt L.K.,University of Strasbourg | And 6 more authors.
Biochimie | Year: 2014

Iron-sulfur (Fe-S) clusters are inorganic cofactors that are ubiquitous and essential. Due to their chemical versatility, Fe-S clusters are implicated in a wide range of protein functions including mitochondrial respiration and DNA repair. Composed of iron and sulfur, they are sensible to oxygen and their biogenesis requires a highly conserved protein machinery that facilitates assembly of the cluster as well as its insertion into apoproteins. Mitochondria are the central cellular compartment for Fe-S cluster biogenesis in eukaryotic cells and the importance of proper function of this biogenesis for life is highlighted by a constantly increasing number of human genetic diseases that are associated with dysfunction of this Fe-S cluster biogenesis pathway. Although these disorders are rare and appear dissimilar, common aspects are found among them. This review will give an overview on what is known on mammalian Fe-S cluster biogenesis today, by putting it into the context of what is known from studies from lower model organisms, and focuses on the associated diseases, by drawing attention to the respective mutations. Finally, it outlines the importance of adequate cellular and murine models to uncover not only each protein function, but to resolve their role and requirement throughout the mammalian organism. © 2014 Elsevier Masson SAS. All rights reserved.


Rhinn M.,Igbmc Institute Of Genetique Et Of Biologie Moleculaire Et Cellulaire | Dolle P.,University of Strasbourg
Development | Year: 2012

Summary Retinoic acid (RA) is a vitamin A-derived, non-peptidic, small lipophilic molecule that acts as ligand for nuclear RA receptors (RARs), converting them from transcriptional repressors to activators. The distribution and levels of RA in embryonic tissues are tightly controlled by regulated synthesis through the action of specific retinol and retinaldehyde dehydrogenases and by degradation via specific cytochrome P450s (CYP26s). Recent studies indicate that RA action involves an interplay between diffusion (morphogen-like) gradients and the establishment of signalling boundaries due to RA metabolism, thereby allowing RA to finely control the differentiation and patterning of various stem/progenitor cell populations. Here, we provide an overview of the RA biosynthesis, degradation and signalling pathways and review the main functions of this molecule during embryogenesis. © 2012. Published by The Company of Biologists Ltd.


Schmucker S.,Igbmc Institute Of Genetique Et Of Biologie Moleculaire Et Cellulaire | Schmucker S.,University of Strasbourg | Schmucker S.,Collège de France | Puccio H.,Igbmc Institute Of Genetique Et Of Biologie Moleculaire Et Cellulaire | And 4 more authors.
Human Molecular Genetics | Year: 2010

Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin. The physiopathological consequences of frataxin deficiency are a severe disruption of iron-sulfur cluster biosynthesis, mitochondrial iron overload coupled to cellular iron dysregulation and an increased sensitivity to oxidative stress. Frataxin is a highly conserved protein, which has been suggested to participate in a variety of different roles associated with cellular iron homeostasis. The present review discusses recent advances that have made crucial contributions in understanding the molecular mechanisms underlying FRDA and in advancements toward potential novel therapeutic approaches. Owing to space constraints, this review will focus on the most commonly accepted and solid molecular and biochemical studies concerning the function of frataxin and the physiopathology of the disease. We invite the reader to read the following reviews to have a more exhaustive overview of the field [Pandolfo, M. and Pastore, A. (2009) The pathogenesis of Friedreich ataxia and the structure and function of frataxin. J. Neurol., 256 (Suppl. 1), 9-17; Gottesfeld, J.M. (2007) Small molecules affecting transcription in Friedreich ataxia. Pharmacol. Ther., 116, 236-248; Pandolfo, M. (2008) Drug insight: antioxidant therapy in inherited ataxias. Nat. Clin. Pract. Neurol., 4, 86-96; Puccio, H. (2009) Multicellular models of Friedreich ataxia. J. Neurol., 256 (Suppl. 1), 18-24]. © The Author 2010. Published by Oxford University Press.


Durand A.,French National Center for Scientific Research | Bonnet J.,French National Center for Scientific Research | Bonnet J.,Max Planck Institute For Biochemie | Fournier M.,French National Center for Scientific Research | And 2 more authors.
Structure | Year: 2014

The molecular organization of the yeast transcriptional coactivator Spt-Ada-Gcn5 acetyltransferase (SAGA) was analyzed by single-particle electron microscopy. Complete or partial deletion of the Sgf73 subunit disconnects the deubiquitination (DUB) module from SAGA and favors in our conditions the cleavage of the C-terminal ends of the Spt7 subunit and the loss of the Spt8 subunit. The structural comparison of the wild-type SAGA with two deletion mutants positioned the DUB module and enabled the fitting of the available atomic models. The localization of the DUB module close to Gcn5 defines a chromatin-binding interface within SAGA, which could be demonstrated by the binding of nucleosome core particles. The TATA-box binding protein (TBP)-interacting subunit Spt8 was found to be located close to the DUB but in a different domain than Spt3, also known to contact TBP. A flexible protein arm brings both subunits close enough to interact simultaneously with TBP. © 2014 Elsevier Ltd.

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