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    Marie-Christine FISCHER

Translational medicine and neurogenetics

Genetic basis of cognitive disorders

Cognitive disorders are responsible for 5-10% of health care costs and are a leading cause of referrals to paediatric, neurological and genetic counselling services.

One of the most prevalent and severe cognitive disorders is intellectual disability. It affects 1-3% of the general population and yet despite its high prevalence, intellectual disability is also one of the least understood and the least investigated of all health problems. Furthermore, it is estimated that genetic mutations account for half of the currently undiagnosed cases, and despite recent successes in identifying some of the mutations responsible, it has been suggested that up to 2500 more genes remain to be identified.

Our general aim is to identify novel human cognition genes and gene networks by screening abnormal anatomy of the mouse brain, ultimately aiming to improve diagnosis and treatment.

We have two general approaches; the first is a genome-wide approach. We have a close collaboration with the International Mouse Phenotyping Consortium (IMPC), which aims at making knockouts for all 20’000 protein coding genes, to systematically study the neuro-anatomy of all IMPC knockout mouse strains in an unbiased manner. The second approach is to apply these mouse knockout resources to well-defined genetic intervals involving intellectual disability such as the 16p11.2 micro-deletion interval that is associated with neurodevelopmental delays and macrocephaly. So far, we have analyzed eight genes encompassing the 16p11.2 locus (Doc2a, Ino80e, Kctd13, Mapk3, Mvp, Prrt2, Sez6l2 and Tbx6).

In parallel to these large-scale genetic studies, we are developing complementary functional approaches, mainly based on the biological understanding of brain malformations, with a particular focus on corpus callosum agenesis, and micro- and macro-cephalies in WD40-repeat genes. We study several of these genes (Wdr37, Wdr47 and Wdr89) in order to understand their function in the central nervous system as well as in the whole organism.

In brief, our laboratory proposes a multidisciplinary approach to advance our understanding of the genetics of cognitive disorders associated with brain malformations. Our research integrates large-scale mouse knockout analysis and is grounded in a strong multidisciplinary perspective, combining mouse and human genetics, and developmental neurobiology.


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    • Binnaz YALCIN - Gutengerg prize - Cercle Gutenberg / Région Alsace - 2015
  • News

  • Publications

    • A knock-in mouse model for KCNQ2-related epileptic encephalopathy displays spontaneous generalized seizures and cognitive impairment.

      Milh M(1)(2), Roubertoux P(1), Biba N(3), Chavany J(1)(2), Spiga Ghata A(1), Fulachier C(1), Collins SC(4), Wagner C(4), Roux JC(1), Yalcin B(4), Félix MS(1), Molinari F(1)(3), Lenck-Santini PP(3), Villard L(1)(5).

      Epilepsia April 2, 2020 .

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

      Ekaterina L Ivanova 1 2 3 4 , Johan G Gilet 1 2 3 4 , Vadym Sulimenko 5 , Arnaud Duchon 1 2 3 4 , Gabrielle Rudolf 1 2 3 4 , Karen Runge 1 2 3 4 , Stephan C Collins 1 2 3 4 6 , Laure Asselin 1 2 3 4 , Loic Broix 1 2 3 4 , Nathalie Drouot 1 2 3 4 , Peggy Tilly 1 2 3 4 , Patrick Nusbaum 7 , Alexandre Vincent 1 2 4 , William Magnant 1 2 4 , Valerie Skory 1 2 3 4 , Marie-Christine Birling 8 , Guillaume Pavlovic 8 , Juliette D Godin 1 2 3 4 , Binnaz Yalcin 1 2 3 4 , Yann Hérault 1 2 3 4 , Pavel Dráber 5 , Jamel Chelly 1 2 3 4 9 10 , Maria-Victoria Hinckelmann 11

      Nature communications 13 May 2019 2019 ; : .

    • Large-scale neuroanatomical study uncovers 198 gene associations in mouse brain morphogenesis.

      Collins SC(1)(2)(3)(4)(5), Mikhaleva A(6), Vrcelj K(7), Vancollie VE(8), Wagner C(1)(2)(3)(4), Demeure N(1)(2)(3)(4), Whitley H(1)(2)(3)(4), Kannan M(1)(2)(3)(4), Balz R(6), Anthony LFE(8), Edwards A(9)(10), Moine H(1)(2)(3)(4), White JK(8), Adams DJ(8), Reymond A(6), Lelliott CJ(8), Webber C(7)(11), Yalcin B(12)(13)(14)(15)(16).

      Nat Commun Aug. 1, 2019 ; 10:3465 .

    • 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 .

    • The neuroanatomy of Eml1 knockout mice, a model of subcortical heterotopia.

      Collins SC(1)(2)(3)(4)(5), Uzquiano A(6)(7)(8), Selloum M(1)(2)(3)(4)(9), Wendling O(1)(2)(3)(4)(9), Gaborit M(1)(2)(3)(4), Osipenko M(1)(2)(3)(4), Birling MC(1)(2)(3)(4)(9), Yalcin B(1)(2)(3)(4), Francis F(6)(7)(8).

      J Anat June 7, 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 .

    • A Syndromic Neurodevelopmental Disorder Caused by Mutations in SMARCD1, a Core SWI/SNF Subunit Needed for Context-Dependent Neuronal Gene Regulation in Flies.

      Nixon KCJ(1), Rousseau J(2), Stone MH(3), Sarikahya M(4), Ehresmann S(2), Mizuno S(5), Matsumoto N(6), Miyake N(6); DDD Study, Baralle D(7), McKee S(8), Izumi K(9), Ritter AL(9), Heide S(10), Heron D(10), Depienne C(11), Titheradge H(12), Kramer JM(13), Campeau PM(14).

      Am J Hum Genet April 4, 2019 ; 104:596-610 .

    • A mutation update for the PCDH19 gene causing early-onset epilepsy in females with an unusual expression pattern.

      Niazi R(1), Fanning EA(1), Depienne C(2)(3)(4), Sarmady M(1)(5), Abou Tayoun AN(6).

      Hum Mutat Mar 2019 ; 40:243-257 .

    • HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond.

      Marini C(1)(2), Porro A(3), Rastetter A(4), Dalle C(4), Rivolta I(5), Bauer D(6), Oegema R(7), Nava C(2)(4)(8), Parrini E(1), Mei D(1), Mercer C(9), Dhamija R(10), Chambers C(11), Coubes C(12), Thevenon J(13), Kuentz P(13)(14), Julia S(15), Pasquier L(16), Dubourg C(17), Carre W(17), Rosati A(1), Melani F(1), Pisano T(1), Giardino M(1), Innes AM(18), Alembik Y(19), Scheidecker S(19), Santos M(20), Figueiroa S(20), Garrido C(20), Fusco C(21), Frattini D(21), Spagnoli C(21), Binda A(5), Granata T(22), Ragona F(22), Freri E(22), Franceschetti S(22), Canafoglia L(22), Castellotti B(22), Gellera C(22), Milanesi R(23), Mancardi MM(24), Clark DR(25), Kok F(26), Helbig KL(27), Ichikawa S(28), Sadler L(29), Neupauerova J(30), Lassuthova P(30), Sterbova K(2)(30), Laridon A(31), Brilstra E(2)(7), Koeleman B(2)(7), Lemke JR(2)(32), Zara F(33), Striano P(2)(34), Soblet J(35)(36)(37), Smits G(35)(36)(37), Deconinck N(38), Barbuti A(23), DiFrancesco D(23), LeGuern E(2)(4)(8), Guerrini R(1)(2), Santoro B(39), Hamacher K(6), Thiel G(40), Moroni A(3), DiFrancesco JC(22)(41), Depienne C(2)(4)(42)(43).

      Brain Nov. 1, 2018 ; 141:3160-3178 .

    • Sixteen diverse laboratory mouse reference genomes define strain-specific haplotypes and novel functional loci.

      Lilue J(1)(2), Doran AG(1)(2), Fiddes IT(3), Abrudan M(2), Armstrong J(3), Bennett R(1), Chow W(2), Collins J(2), Collins S(4)(5), Czechanski A(6), Danecek P(2), Diekhans M(3), Dolle DD(2), Dunn M(2), Durbin R(2)(7), Earl D(3), Ferguson-Smith A(7), Flicek P(1)(2), Flint J(8), Frankish A(1)(2), Fu B(2), Gerstein M(9), Gilbert J(2), Goodstadt L(10), Harrow J(2), Howe K(2), Ibarra-Soria X(2), Kolmogorov M(11), Lelliott CJ(2), Logan DW(2), Loveland J(1)(2), Mathews CE(12), Mott R(13), Muir P(9), Nachtweide S(14), Navarro FCP(9), Odom DT(15)(16), Park N(2), Pelan S(2), Pham SK(17), Quail M(2), Reinholdt L(6), Romoth L(14), Shirley L(2), Sisu C(9)(18), Sjoberg-Herrera M(19), Stanke M(14), Steward C(2), Thomas M(2), Threadgold G(2), Thybert D(1)(20), Torrance J(2), Wong K(2), Wood J(2), Yalcin B(4), Yang F(2), Adams DJ(2), Paten B(3), Keane TM(21)(22)(23).

      Nat Genet Nov 2018 ; 50:1574-1583 .

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