The Team
  • Researchers

    Jamel CHELLY

    Anne DE SAINT-MARTIN

    Edouard Franck HIRSCH

    Béatrice LANNES

    Jean-Louis MANDEL

    Hervé MOINE

    Amélie PITON

  • Post-Doctoral Fellows

    Florent COLIN

    Maria Victoria HINCKELMANN RIVAS

  • PhD Students

    Jérémie COURRAUD

    Johan GILET

    Karima HABBAS-BERKIOUI

  • Engineers & Technicians

    Nathalie DROUOT

    Eric FLATTER

    Gabrielle RUDOLF

    Valérie SKORY

  • Trainee

    Meriam HADJ AMOR

Translational medicine and neurogenetics

Genetics and pathophysiology of neurodevelopmental and Epileptogenic Disorders

Neurodevelopmental diseases (NDDs) are a group of conditions with onset in the developmental period, consequence of anomalies that occurred during brain development and impair normal brain functioning. NDDs encompass intellectual disability (ID), autism spectrum disorders (ASD), epileptic encephalopathies (EE), focal cortical dysplasias (FCDs), and malformations of cortical development (MCD). More than 1,000 genes are known to be involved in monogenic forms of NDDs, encoding proteins belonging to different pathways, and more remain to be identified. Except for a few monogenic forms (such as Fragile X syndrome, caused by mutation in the FMR1 gene) the genotype/phenotype correlations and the natural evolution of patients affected by these different genetic entities are not always well described, and little is known about the pathophysiological mechanisms involved. This knowledge is essential to improve care for patients and consider possible therapeutic perspectives.

 

The identification and functional study of genes involved in NDDs is essential for precise molecular diagnosis and for genetic counseling in affected families, and allow the identification of major players and novel mechanisms important for neural development, higher brain functions and regulation of synaptic plasticity.

 

We perform genetic and genomic investigations aiming at identifying genes and genetic causes involved in intellectual disability autism spectrum disorders, epileptic encephalopathies or malformations of cortical development. We study focal cortical dysplasia disorders (FCD), often associated with intractable epilepsy, and we explore genetic hypotheses that might shed lights on the pathophysiological mechanisms of these poorly understood disorders.

 

We are developing genetic and functional tools to better diagnose these NDDs and we are building a participatory online database to collect clinical information specific for each monogenic forms of ID (Genida project). We dissect pathophysiological mechanisms of some frequent monogenic forms of NDD, affecting proteins involved in the regulation of gene expression at the transcriptional or posttranscriptional level (RNA binding proteins).

 

We notably investigate the mechanism by which the lack of FMRP leads to Fragile-X syndrome (the most frequent monogenic cause of ID) by dysregulating the expression of neuronal mRNAs, and we test the importance of diacylglycerol kinase, a main mRNA target of FMRP, as therapeutic target.  We also pursue efforts to better understand pathophysiological mechanisms underlying malformations of cortical development resulting from mutations in tubulins and microtubule-dependent proteins (i.e. KIF5C, KIF2A, DYNC1H1 and TUBG1). We use cellular models as well as in vivo approaches to study cortex development in animal models (knock-in and knock-out mouse models, or inactivation by RNA interference using in utero electroporation).

 

The team has very close interaction, including dual affiliation (J. Chelly, A. Piton) with the genetic diagnostic laboratory at Strasbourg Academic Hospital (CHU), as well as with the services of Medical Genetics, Adult and Child Neurology, Child Psychiatry, favoring translational applications of research results and interactions with clinicians and patients families.

  • Current projects

    - Identification of genetic bases of epilepsy and cortical malformations (EE, MCD, FCD) (Jamel Chelly)

    - Identification of novel genes implicated in ID and ASD, their mutation mechanisms and the corresponding clinical features; characterization of pathophysiological mechanisms involved in some frequent monogenic forms using cellular models and trancriptomics (Amélie Piton, Jean-Louis Mandel)

    - Collecting in a participatory online database genotype/phenotype correlation data and natural history for monogenic forms of ID/ASD (Florent Colin, Jean-Louis Mandel)

    - Development and transfer of efficient genetic and functional tools for better diagnosis of heterogeneous groups of NDDs (Amélie Piton, Jean-Louis Mandel, Jamel Chelly)

    - Study the contributions of genetic, epigenetic and transcriptional abnormalities in the pathogenesis of FCD (Jamel Chelly)

    - Characterize and understand the pathophysiological mechanisms involved in MCD using cellular and mouse models for the Tubg1, Kif2a, Tubg1 and Nedd4l genes (Jamel Chelly)

    - Characterize and understand the pathophysiological mechanisms involved in Fragile-X syndrome using cellular and mouse models (Fmrp, Dgkk)(Hervé Moine)

    - Preclinical testing of novel therapeutic approaches forFragile-X syndrome (Hervé Moine)

    - Understanding the excess of males affected by NDDs by studying the role of androgens in neural precursors (Amélie Piton, Jean-Louis Mandel)

  • Collaborations

    Projects and investigations driven collaborations with groups at the IGBMC:

    • Juliette Godin, Christel Golzio, Binnaz Yalcin, Izabella Sumara and Yann Herault.
    • Nadia Bahi Buisson (Hôpital Necker – IMAGINE. Paris, France
    • )Renzo Guerrini (Children's Hospital A. Meyer-University of Florence)
    • Izzie Jacques Namer, Service de Neuroimagerie, Hôpital de Hautepierre. Strasbourg. France
    • Vincent Laugel, Anne de St Martin (Service de Pédiatrie, Hôpital de Hautepierre. Strasbourg. France)
    • Carmen Schroder, Romain Coutelle (Service de Pédo-Psychiatrie, CHU Strasbourg)
    • Mathieu Anheim,  Christine Tranchant (Service de Neurologie, Hôpital de Hautepierre. Strasbourg. France)
    • Hélène Dollfus, Elise Schafer, Salima El Chehadeh, Yves Alembik (Service de Génétique Médicale, Hôpital de Hautepierre , Strasbourg, France)
    • Pierre Parrend (iCube, CNRS and U. of Strasbourg)
    • Thierry Bienvenu, Pierre Billuart (Institut Cochin, Paris France)
    • Damien Sanlaville, Gaetan Lesca (Hospices Civils de Lyon – Lyon. France)
    • Joseph Gleeson (Dept. Neurosciences and Pediatrics, University of California, San Diego).
    • Nicolas Cowan (NY University, USA)
    • Frédéric Saudou (CEA, Grenoble. France)
    • Laurent Nguyen (GIGA - Neurosciences, Université de Liège. Belgique)
    • David Keays (Institute of Molecular Pathology, Vienna. Austria)
    • DESIRE partners (http://epilepsydesireproject.eu/)
    • Alexandra Benchoua (Istem, Evry, France)
    • Michael Lombardo, Simon Baron-Cohen (Cambridge Neuroscience)
    • Dominique Weil, Marianne Bénard (IBPS, Paris)
    • David Koolen, Tjitske Kleefstra (Radboud University, Nijmegen, Holland)
  • Prizes/Awards

    • Angélique QUARTIER - Prix de Thèse - Société de Biologie de Strasbourg - 2018
    • Loïc BROIX - Prix de Thèse - Chancellerie des Universités de Paris - 2017
    • Ricardos MATTIOLI - Prix jeune Chercheur - Fondation Jérôme Lejeune - 2017
    • Ricardos Tabet - Young Researcher Prize – Jérôme Lejeune - Fondation Jérôme Lejeune - 2015
    • Claire REDIN - Thesis Prize - Société des Amis des Universités de l'Académie de Strasbourg - 2015
    • Jamel CHELLY - Scientific prize - Fondation NRJ - Institut de France - 2014
    • Claire REDIN - Prix Christian Nezelof Jeune Chercheur - Association Française de Recherche en Pathologie Pédiatrique - 2014
    • Jamel CHELLY - Laureate - Fondation JED - 2013
    • Jamel CHELLY - Research prize - Inserm - 2010
    • Jean-Louis MANDEL - Scientific Prize - Académie Nationale de Médecine - 2009
    • Jean-Louis MANDEL - Chevalier of the Legion of Honour - Etat français - 2008
    • Jean-Louis MANDEL - Professor at the College of France - Collège de France - 2004
    • Jean-Louis MANDEL - Neuronal Plasticity Prize - Fondation IPSEN - 2004
    • Jamel CHELLY - Silver Medal - CNRS - 2002
    • Jamel CHELLY - Grand prize - EDF - 2001
    • Jean-Louis MANDEL - Klaus Joachim Zülch prize for research in neurology - Foundation Reemtsma / Max Planck Society - 2001
    • Jamel CHELLY - Research prize "Life science" - Fondation Bettencourt Schueller - 1999
    • Jean-Louis MANDEL - Member of the French Academy of science - Académie des sciences - 1999
    • Jamel CHELLY - Medicale and scientific research award - Fondation pour la Recherche Médicale (FRM) - 1999
    • Jean-Louis MANDEL - Louis-Jeantet medicine prize - Fondation Louis-Jeantet - 1999
    • Jean-Louis MANDEL - Mauro Baschirotto prize - Société Européenne de Génétique Humaine - 1998
    • Jean-Louis MANDEL - Richard Lounsbery Prize - Académie des sciences (France) / National Academy of Sciences (États-Unis) - 1994
    • Jamel CHELLY - Bronze medal - CNRS - 1992
    • Jean-Louis MANDEL - San Remo International prize for genetic research - Société Italienne de Génétique Humaine - 1992
    • Jamel CHELLY - Carré-Bessault prize - Académie des sciences - 1992
    • Jean-Louis MANDEL - GPA Foundation prize - Académie des sciences - 1988
    • Jean-Louis MANDEL - Member of the European Molecular Biology Organization (EMBO) - European Molecular Biology Organization (EMBO) - 1982
  • News

  • Publications

    • IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients.

      Mignot C(1)(2), McMahon AC(3), Bar C(4)(5)(6), Campeau PM(7), Davidson C(3), Buratti J(8), Nava C(9)(8), Jacquemont ML(10), Tallot M(10), Milh M(11)(12), Edery P(13)(14)(15), Marzin P(8), Barcia G(5)(6)(16), Barnerias C(17), Besmond C(5)(6), Bienvenu T(18)(19), Bruel AL(20)(21), Brunga L(22), Ceulemans B(23), Coubes C(24), Cristancho AG(25), Cunningham F(3), Dehouck MB(26), Donner EJ(22), Duban-Bedu B(26), Dubourg C(27), Gardella E(28)(29), Gauthier J(7), Genevieve D(24)(30), Gobin-Limballe S(16), Goldberg EM(25), Hagebeuk E(31), Hamdan FF(7), Hancarova M(32), Hubert L(5)(6), Ioos C(33), Ichikawa S(34), Janssens S(35), Journel H(36), Kaminska A(37), Keren B(8), Koopmans M(38), Lacoste C(39), Lassuthova P(40), Lederer D(41), Lehalle D(20)(42), Marjanovic D(28), Metreau J(43), Michaud JL(7), Miller K(44), Minassian BA(22), Morales J(3), Moutard ML(45)(46), Munnich A(5)(6)(16), Ortiz-Gonzalez XR(25), Pinard JM(47), Prchalova D(32), Putoux A(13)(14)(15), Quelin C(48), Rosen AR(25), Roume J(49), Rossignol E(50), Simon MEH(38), Smol T(51), Shur N(44), Shelihan I(7), Sterbova K(40), Vyhnalkova E(32), Vilain C(52)(53)(54), Soblet J(52)(53)(54), Smits G(52)(53)(54), Yang SP(55), van der Smagt JJ(38), van Hasselt PM(56), van Kempen M(38), Weckhuysen S(57)(58), Helbig I(25), Villard L(12)(39), Heron D(8), Koeleman B(38), Mller RS(27)(28), Lesca G(13)(14)(15), Helbig KL(25), Nabbout R(4)(5)(6), Verbeek NE(38), Depienne C(59)(60)(61).

      Genet Med Apr 2019 ; 21:837-849 .

    • New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome.

      Chater-Diehl E(1), Ejaz R(2), Cytrynbaum C(1)(3)(4), Siu MT(1), Turinsky A(1)(5), Choufani S(1), Goodman SJ(1), Abdul-Rahman O(6), Bedford M(7)(8), Dorrani N(9), Engleman K(10), Flores-Daboub J(11), Genevieve D(12), Mendoza-Londono R(1)(3)(13), Meschino W(7), Perrin L(14), Safina N(15)(16)(17), Townshend S(18), Scherer SW(1)(4)(19)(20), Anagnostou E(21)(22), Piton A(23)(24), Deardorff M(25)(26), Brudno M(1)(5)(27), Chitayat D(3)(4)(28), Weksberg R(29)(30)(31)(32).

      BMC Med Genomics July 9, 2019 ; 12:105 .

    • A novel heterozygous ANO3 mutation responsible for myoclonic dystonia.

      Laurencin C(1), Broussolle E(2), Danaila T(3), Anheim M(4), Chelly J(5), Thobois S(2).

      J Neurol Sci June 13, 2019 ; 403:65-66 .

    • Novel mutations in NLGN3 causing autism spectrum disorder and cognitive impairment.

      Quartier A(1)(2)(3)(4), Courraud J(1)(2)(3)(4), Thi Ha T(5)(6), McGillivray G(7), Isidor B(8), Rose K(9), Drouot N(1)(2)(3)(4), Savidan MA(1)(2)(3)(4), Feger C(10), Jagline H(1)(2)(3)(4), Chelly J(1)(2)(3)(4)(10), Shaw M(2), Laumonnier F(11)(12), Gecz J(5)(6), Mandel JL(1)(2)(3)(4)(13), Piton A(1)(2)(3)(4)(10).

      Hum Mutat June 10, 2019 .

    • TUBG1 missense variants underlying cortical malformations disrupt neuronal locomotion and microtubule dynamics but not neurogenesis.

      Ivanova EL(1)(2)(3)(4), Gilet JG(1)(2)(3)(4), Sulimenko V(5), Duchon A(1)(2)(3)(4), Rudolf G(1)(2)(3)(4), Runge K(1)(2)(3)(4), Collins SC(1)(2)(3)(4)(6), Asselin L(1)(2)(3)(4), Broix L(1)(2)(3)(4), Drouot N(1)(2)(3)(4), Tilly P(1)(2)(3)(4), Nusbaum P(7), Vincent A(1)(2)(4), Magnant W(1)(2)(4), Skory V(1)(2)(3)(4), Birling MC(8), Pavlovic G(8), Godin JD(1)(2)(3)(4), Yalcin B(1)(2)(3)(4), Herault Y(1)(2)(3)(4), Draber P(5), Chelly J(1)(2)(3)(4)(9)(10), Hinckelmann MV(11)(12)(13)(14).

      Nat Commun May 13, 2019 ; 10:2129 .

    • Novel anoctamin-3 missense mutation responsible for early-onset myoclonic dystonia.

      Delamarre A(1), Chelly J(2), Guehl D(3), Drouot N(4), Tranchant C(5), Anheim M(5), Burbaud P(3).

      Parkinsonism Relat Disord April 26, 2019 .

    • Protocol GenoDENT: Implementation of a New NGS Panel for Molecular Diagnosis of Genetic Disorders with Orodental Involvement.

      Rey T(1)(2), Tarabeux J(2), Gerard B(2), Delbarre M(2), Le Bechec A(3), Stoetzel C(4), Prasad M(4), Laugel-Haushalter V(4), Kawczynski M(1)(5), Muller J(2)(4), Chelly J(2)(6), Dollfus H(4), Maniere MC(1)(5), Bloch-Zupan A(7)(8)(9)(10)(11).

      Methods Mol Biol 2019 ; 1922:407-452 .

    • Mild malformations of cortical development in sleep-related hypermotor epilepsy due to KCNT1 mutations.

      Rubboli G(1)(2), Plazzi G(3)(4), Picard F(5), Nobili L(6), Hirsch E(7), Chelly J(8), Prayson RA(9), Boutonnat J(10), Bramerio M(11), Kahane P(12), Dibbens LM(13), Gardella E(1)(14), Baulac S(15)(16)(17), Mller RS(1)(14).

      Ann Clin Transl Neurol Dec. 25, 2018 ; 6:386-391 .

    • ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder.

      Carapito R(1), Ivanova EL(2), Morlon A(3), Meng L(4), Molitor A(5), Erdmann E(2), Kieffer B(2), Pichot A(5), Naegely L(5), Kolmer A(5), Paul N(5), Hanauer A(5), Tran Mau-Them F(6), Jean-Marcais N(6), Hiatt SM(7), Cooper GM(7), Tvrdik T(8), Muir AM(9), Dimartino C(10), Chopra M(11), Amiel J(12), Gordon CT(10), Dutreux F(5), Garde A(6), Thauvin-Robinet C(6), Wang X(4), Leduc MS(4), Phillips M(13), Crawford HP(13), Kukolich MK(13), Hunt D(14), Harrison V(14), Kharbanda M(14); Deciphering Developmental Disorders Study(15); University of Washington Center for Mendelian Genomics, Smigiel R(16), Gold N(17), Hung CY(17), Viskochil DH(18), Dugan SL(18), Bayrak-Toydemir P(19), Joly-Helas G(20), Guerrot AM(20), Schluth-Bolard C(21), Rio M(22), Wentzensen IM(23), McWalter K(23), Schnur RE(23), Lewis AM(24), Lalani SR(24), Mensah-Bonsu N(25), Ceraline J(26), Sun Z(27), Ploski R(28), Bacino CA(24), Mefford HC(9), Faivre L(6), Bodamer O(29), Chelly J(30), Isidor B(31), Bahram S(32).

      Am J Hum Genet Dec. 26, 2018 .

    • GRIN2A-related disorders: genotype and functional consequence predict phenotype.

      Strehlow V(1), Heyne HO(1)(2)(3), Vlaskamp DRM(4)(5), Marwick KFM(6), Rudolf G(7)(8)(9)(10), de Bellescize J(11), Biskup S(12), Brilstra EH(13), Brouwer OF(4), Callenbach PMC(4), Hentschel J(1), Hirsch E(8)(9)(10)(14), Kind PC(6)(15)(16), Mignot C(17)(18)(19), Platzer K(1), Rump P(5), Skehel PA(6), Wyllie DJA(6)(15)(16); GRIN2A study group, Hardingham GE(6)(15)(20), van Ravenswaaij-Arts CMA(5), Lesca G(21)(22)(23), Lemke JR(1).

      Brain Dec. 12, 2018 .

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