The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism.

Dexter Hadley 1 Zhi Liang Wu 1 Charlly Kao 1 Akshata Kini 1 Alisha Mohamed-Hadley 1 Kelly Thomas 1 Lyam Vazquez 1 Haijun Qiu 1 Frank Mentch 1 Renata Pellegrino 1 Cecilia Kim 1 John Connolly 1 Dalila Pinto 2, 3, 4, 5, 6, 7 Alison Merikangas 8 Lambertus Klei 9 Jacob Vorstman 10 Ann Thompson 11 Regina Regan 12, 13 Alistair Pagnamenta 14 Barbara Oliveira 15, 16 Tiago Magalhaes 12, 13 John Gilbert 17 Eftichia Duketis 18 Maretha De Jonge 10 Michael Cuccaro 17 Catarina Correia 15, 16 Judith Conroy 12, 19 Inês Conceição 15, 16 Andreas Chiocchetti 18 Jillian Casey 12, 13 Nadia Bolshakova 8 Elena Bacchelli 20 Richard Anney 8 Lonnie Zwaigenbaum 21 Kerstin Wittemeyer 22 Simon Wallace 23 Herman Van Engeland 10 Latha Soorya 2, 3 Bernadette Rogé 24 Wendy Roberts 25 Fritz Poustka 18 Susana Mouga 26, 27 Nancy Minshew 9 Susan Mcgrew 28 Catherine Lord 29 Marion Leboyer 30, 31, 32 Ann Le Couteur 33 Alexander Kolevzon 2, 3, 7 Suma Jacob 34 Stephen Guter 34 Jonathan Green 35, 36 Andrew Green 12, 37 Christopher Gillberg 38 Bridget Fernandez 39 Frederico Duque 26, 27 Richard Delorme 32, 40, 41 Geraldine Dawson 42 Cátia Café 26 Sean Brennan 8 Thomas Bourgeron 32, 40, 43 Patrick Bolton 44, 45 Sven Bölte 18 Raphael Bernier 46 Gillian Baird 47 Anthony Bailey 48, 49 Evdokia Anagnostou 50 Joana Almeida 26 Ellen Wijsman 51, 52 Veronica Vieland 53 Astrid Vicente 15, 54 Gerard Schellenberg 55 Margaret Pericak-Vance 17 Andrew Paterson 56 Jeremy Parr 57 Guiomar Oliveira 26, 27 John Nurnberger 58 Anthony Monaco 14 Elena Maestrini 20 Sabine Klauck 59 Jonathan Haines 60, 61 Daniel Geschwind 62 Christine Freitag 18 Susan Folstein 63 Sean Ennis 12 Hilary Coon 64 Agatino Battaglia 65 Peter Szatmari 11 James Sutcliffe 60, 61 Joachim Hallmayer 66 Michael Gill 67 Edwin Cook 68 Joseph Buxbaum 69, 70, 71, 72, 73, 74 Bernie Devlin 9 Louise Gallagher 67 Catalina Betancur 75 Stephen Scherer 56, 76 Joseph Glessner 1 Hakon Hakonarson 1, 77, *
* Auteur correspondant
Abstract : Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions.
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Article dans une revue
Nature Communications, Nature Publishing Group, 2014, 5, pp.4074. 〈10.1038/ncomms5074〉
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Dernière modification le : jeudi 11 janvier 2018 - 14:27:03
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Dexter Hadley, Zhi Liang Wu, Charlly Kao, Akshata Kini, Alisha Mohamed-Hadley, et al.. The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism.. Nature Communications, Nature Publishing Group, 2014, 5, pp.4074. 〈10.1038/ncomms5074〉. 〈inserm-01009668〉

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