Journal ArticleDOI
Dysfunction of SHANK2 and CHRNA7 in a patient with intellectual disability and language impairment supports genetic epistasis of the two loci
B Chilian,Hengameh Abdollahpour,Tatjana Bierhals,I Haltrich,György Fekete,Inga Nagel,Georg Rosenberger,Kerstin Kutsche +7 more
TLDR
Co‐occurrence of a de novo SHANK2 mutation and a CHRNA7 duplication in two reported patients with ASD and ID as well as in the patient with t(11;17;19), severe ID and behavior problems suggests convergence of these genes on a common synaptic pathway.Abstract:
Synaptopathies constitute a group of neurological diseases including autism spectrum disorders (ASD) and intellectual disability (ID). They have been associated with mutations in genes encoding proteins important for the formation and stabilization of synapses, such as SHANK1-3. Loss-of-function mutations in the SHANK genes have been identified in individuals with ASD and ID suggesting that other factors modify the neurological phenotype. We report a boy with severe ID, behavioral anomalies, and language impairment who carries a balanced de novo triple translocation 46,XY,t(11;17;19)(q13.3;q25.1;q13.42). The 11q13.3 breakpoint was found to disrupt the SHANK2 gene. The patient also carries copy number variations at 15q13.3 and 10q22.11 encompassing ARHGAP11B and two synaptic genes. The CHRNA7 gene encoding α7-nicotinic acetylcholine receptor subunit and the GPRIN2 gene encoding G-protein-regulated inducer of neurite growth 2 were duplicated. Co-occurrence of a de novo SHANK2 mutation and a CHRNA7 duplication in two reported patients with ASD and ID as well as in the patient with t(11;17;19), severe ID and behavior problems suggests convergence of these genes on a common synaptic pathway. Our results strengthen the oligogenic inheritance model and highlight the presence of a large effect mutation and modifier genes collectively determining phenotypic expression of the synaptopathy.read more
Citations
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Journal ArticleDOI
Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments
Claire S. Leblond,Caroline Nava,Anne Polge,Julie Gauthier,Guillaume Huguet,Serge Lumbroso,Fabienne Giuliano,Coline Stordeur,Christel Depienne,Kevin Mouzat,Dalila Pinto,Jennifer L. Howe,Nathalie Lemière,Christelle M. Durand,Jessica Guibert,Elodie Ey,Roberto Toro,Hugo Peyre,Alexandre Mathieu,Frédérique Amsellem,Maria Råstam,I. Carina Gillberg,Gudrun A. Rappold,Richard Holt,Anthony P. Monaco,Elena Maestrini,Pilar Galan,Delphine Héron,Aurélia Jacquette,Alexandra Afenjar,Agnès Rastetter,Alexis Brice,Françoise Devillard,Brigitte Assouline,Fanny Laffargue,James Lespinasse,Jean Chiesa,François Rivier,Dominique Bonneau,Béatrice Regnault,Diana Zelenika,Marc Delepine,Mark Lathrop,Damien Sanlaville,Caroline Schluth-Bolard,Patrick Edery,Laurence Perrin,Anne Claude Tabet,Michael J. Schmeisser,Tobias M. Boeckers,Mary Coleman,Daisuke Sato,Peter Szatmari,Stephen W. Scherer,Guy A. Rouleau,Catalina Betancur,Marion Leboyer,Christopher Gillberg,Richard Delorme,Thomas Bourgeron +59 more
TL;DR: Mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment and the clinical relevance of these genes remains to be ascertained.
Journal ArticleDOI
The emerging role of SHANK genes in neuropsychiatric disorders
Audrey Guilmatre,Audrey Guilmatre,Guillaume Huguet,Guillaume Huguet,Richard Delorme,Thomas Bourgeron,Thomas Bourgeron +6 more
TL;DR: Based on neuropathological findings in animal models and patients, a possible role of SHANK in Alzheimer's disease is discussed and information is provided to further investigate the role of the SHANK genes in neuropsychiatric disorders.
Journal ArticleDOI
Shank synaptic scaffold proteins: keys to understanding the pathogenesis of autism and other synaptic disorders.
TL;DR: The major genetic, molecular, behavior and electrophysiological studies that provide new clues into the function of Shanks are summarized and pave the way for the discovery of new therapeutic drugs targeted to treat patients with SHANK mutations and also patients affected by other neurodevelopmental and neuropsychiatric disorders.
Journal ArticleDOI
The human clinical phenotypes of altered CHRNA7 copy number.
TL;DR: Copy number variants have been implicated in multiple neuropsychiatric conditions, including autism spectrum disorder (ASD), schizophrenia, and intellectual disability, and Chromosome 15q13 is a hotspot for such CNVs due to the presence of low copy repeat (LCR) elements, which facilitate non-allelic homologous recombination (NAHR).
Journal ArticleDOI
Subchronic treatment of donepezil rescues impaired social, hyperactive, and stereotypic behavior in valproic acid-induced animal model of autism.
Ji-Woon Kim,Hana Seung,Kyung Ja Kwon,Mee Jung Ko,Eun Joo Lee,Hyun Ah Oh,Chang Soon Choi,Ki Chan Kim,Edson Luck Gonzales,Jueng Soo You,Dong-Hee Choi,Jongmin Lee,Seol-Heui Han,Sung Min Yang,Jae Hoon Cheong,Chan Young Shin,Geon Ho Bahn +16 more
TL;DR: Evidence is provided that dysregulation of ACh system represented by the up-regulation of acetylcholinesterase (AChE) may serve as an effective pharmacological therapeutic target against autistic behaviors in VPA animal model of ASD, which should be subjected for further investigation to verify the clinical relevance.
References
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Journal ArticleDOI
Functional impact of global rare copy number variation in autism spectrum disorders
Dalila Pinto,Alistair T. Pagnamenta,Lambertus Klei,Richard Anney,Daniele Merico,Regina Regan,Judith Conroy,Tiago R. Magalhaes,Tiago R. Magalhaes,Catarina Correia,Catarina Correia,Brett S. Abrahams,Joana Almeida,Elena Bacchelli,Gary D. Bader,Anthony J. Bailey,Gillian Baird,Agatino Battaglia,Tom Berney,Nadia Bolshakova,Sven Bölte,Patrick Bolton,Thomas Bourgeron,Sean Brennan,Jessica Brian,Susan E. Bryson,Andrew R. Carson,Guillermo Casallo,Jillian P. Casey,Brian H.Y. Chung,Lynne E Cochrane,Christina Corsello,Emily L. Crawford,Andrew Crossett,Cheryl Cytrynbaum,Geraldine Dawson,Maretha de Jonge,Richard Delorme,Irene Drmic,Eftichia Duketis,Frederico Duque,Annette Estes,Penny Farrar,Bridget A. Fernandez,Susan E. Folstein,Eric Fombonne,Christine M. Freitag,John Gilbert,Christopher Gillberg,Joseph T. Glessner,Jeremy Goldberg,Andrew Green,Jonathan Green,Stephen J. Guter,Hakon Hakonarson,Elizabeth A. Heron,Matthew Hill,Richard Holt,Jennifer L. Howe,Gillian Hughes,Vanessa Hus,Roberta Igliozzi,Cecilia Kim,Sabine M. Klauck,Alexander Kolevzon,Olena Korvatska,Vlad Kustanovich,Clara Lajonchere,Janine A. Lamb,Magdalena Laskawiec,Marion Leboyer,Ann Le Couteur,Bennett L. Leventhal,Anath C. Lionel,Anath C. Lionel,Xiao-Qing Liu,Catherine Lord,Linda Lotspeich,Sabata C. Lund,Elena Maestrini,William M. Mahoney,Carine Mantoulan,Christian R. Marshall,Helen McConachie,Christopher J. McDougle,Jane McGrath,William M. McMahon,Alison K. Merikangas,Ohsuke Migita,Nancy J. Minshew,Ghazala Mirza,Jeff Munson,Stanley F. Nelson,Carolyn Noakes,Abdul Noor,Gudrun Nygren,Guiomar Oliveira,Katerina Papanikolaou,Jeremy R. Parr,Barbara Parrini,Tara Paton,Andrew Pickles,Marion Pilorge,Joseph Piven,Chris P. Ponting,David J. Posey,Annemarie Poustka,Fritz Poustka,Aparna Prasad,Jiannis Ragoussis,Katy Renshaw,Jessica Rickaby,Wendy Roberts,Kathryn Roeder,Bernadette Rogé,Michael Rutter,Laura J. Bierut,John P. Rice,Jeff Salt,Katherine Sansom,Daisuke Sato,Ricardo Segurado,Ana Filipa Sequeira,Lili Senman,Lili Senman,Naisha Shah,Val C. Sheffield,Latha Soorya,Inês Sousa,Olaf Stein,Nuala Sykes,Vera Stoppioni,Christina Strawbridge,Raffaella Tancredi,Katherine E. Tansey,Bhooma Thiruvahindrapduram,Ann P. Thompson,Susanne Thomson,Ana Tryfon,John Tsiantis,Herman Van Engeland,John B. Vincent,Fred R. Volkmar,Simon Wallace,Kai Wang,Zhouzhi Wang,Thomas H. Wassink,Caleb Webber,Rosanna Weksberg,Kirsty Wing,Kerstin Wittemeyer,Shawn Wood,Jing Wu,Brian L. Yaspan,Danielle Zurawiecki,Lonnie Zwaigenbaum,Joseph D. Buxbaum,Rita M. Cantor,Edwin H. Cook,Hilary Coon,Michael L. Cuccaro,Bernie Devlin,Sean Ennis,Louise Gallagher,Daniel H. Geschwind,Michael Gill,Jonathan L. Haines,Joachim Hallmayer,Judith Miller,Anthony P. Monaco,John I. Nurnberger,Andrew D. Paterson,Margaret A. Pericak-Vance,Gerard D. Schellenberg,Peter Szatmari,Astrid M. Vicente,Veronica J. Vieland,Veronica J. Vieland,Ellen M. Wijsman,Stephen W. Scherer,James S. Sutcliffe,Catalina Betancur +181 more
TL;DR: The genome-wide characteristics of rare (<1% frequency) copy number variation in ASD are analysed using dense genotyping arrays to reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
Journal ArticleDOI
Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.
Christelle M. Durand,Catalina Betancur,Tobias M. Boeckers,Juergen Bockmann,Pauline Chaste,Fabien Fauchereau,Gudrun Nygren,Maria Råstam,I. Carina Gillberg,Henrik Anckarsäter,Eili Sponheim,Hany Goubran-Botros,Richard Delorme,Nadia Chabane,Marie-Christine Mouren-Simeoni,Philippe de Mas,Eric Bieth,Bernadette Rogé,Delphine Héron,Lydie Burglen,Christopher Gillberg,Marion Leboyer,Thomas Bourgeron +22 more
TL;DR: It is reported that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders.
Journal ArticleDOI
Deep sequencing reveals 50 novel genes for recessive cognitive disorders
Hossein Najmabadi,Hao Hu,Masoud Garshasbi,Tomasz Zemojtel,Seyedeh Sedigheh Abedini,Wei Chen,Masoumeh Hosseini,Farkhondeh Behjati,Stefan A. Haas,Payman Jamali,Agnes Zecha,Marzieh Mohseni,Lucia Püttmann,Leyla Nouri Vahid,C Jensen,Lia Abbasi Moheb,M Bienek,Farzaneh Larti,Ines Mueller,Robert Weissmann,Hossein Darvish,Klaus Wrogemann,Klaus Wrogemann,Valeh Hadavi,Bettina Lipkowitz,Sahar Esmaeeli-Nieh,Dagmar Wieczorek,Roxana Kariminejad,Saghar Ghasemi Firouzabadi,Monika Cohen,Zohreh Fattahi,Imma Rost,Faezeh Mojahedi,Christoph Hertzberg,Atefeh Dehghan,Anna Rajab,Mohammad Javad Soltani Banavandi,Julia Hoffer,Masoumeh Falah,Luciana Musante,Vera M. Kalscheuer,Reinhard Ullmann,Andreas W. Kuss,Andreas Tzschach,Kimia Kahrizi,Hans-Hilger Ropers +45 more
TL;DR: This study, the largest published so far, has revealed additional mutations in 23 genes previously implicated in intellectual disability or related neurological disorders, as well as single, probably disease-causing variants in 50 novel candidate genes.
Journal ArticleDOI
Intellectual disability and its relationship to autism spectrum disorders.
TL;DR: Current status and future directions for better understanding these two covarying disorders was reviewed along with a discussion of relevant strengths and weaknesses of the current body of research.
Journal ArticleDOI
Contribution of SHANK3 Mutations to Autism Spectrum Disorder
Rainald Moessner,Christian R. Marshall,James S. Sutcliffe,Jennifer Skaug,Dalila Pinto,John B. Vincent,Lonnie Zwaigenbaum,Bridget A. Fernandez,Wendy Roberts,Peter Szatmari,Stephen W. Scherer +10 more
TL;DR: The combined data provide support that haploinsufficiency of SHANK3 can cause a monogenic form of autism in sufficient frequency to warrant consideration in clinical diagnostic testing.
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Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2
Michael J. Schmeisser,Elodie Ey,Stephanie Wegener,Juergen Bockmann,A. Vanessa Stempel,Angelika Kuebler,Anna-Lena Janssen,Patrick T Udvardi,Ehab Shiban,Christina Spilker,Detlef Balschun,Boris V. Skryabin,Susanne tom Dieck,Karl-Heinz Smalla,Dirk Montag,Claire S. Leblond,Philippe Faure,Nicolas Torquet,Anne-Marie Le Sourd,Roberto Toro,Andreas M. Grabrucker,Sarah A. Shoichet,Dietmar Schmitz,Michael R. Kreutz,Thomas Bourgeron,Eckart D. Gundelfinger,Tobias M. Boeckers +26 more
Functional impact of global rare copy number variation in autism spectrum disorders
Dalila Pinto,Alistair T. Pagnamenta,Lambertus Klei,Richard Anney,Daniele Merico,Regina Regan,Judith Conroy,Tiago R. Magalhaes,Tiago R. Magalhaes,Catarina Correia,Catarina Correia,Brett S. Abrahams,Joana Almeida,Elena Bacchelli,Gary D. Bader,Anthony J. Bailey,Gillian Baird,Agatino Battaglia,Tom Berney,Nadia Bolshakova,Sven Bölte,Patrick Bolton,Thomas Bourgeron,Sean Brennan,Jessica Brian,Susan E. Bryson,Andrew R. Carson,Guillermo Casallo,Jillian P. Casey,Brian H.Y. Chung,Lynne E Cochrane,Christina Corsello,Emily L. Crawford,Andrew Crossett,Cheryl Cytrynbaum,Geraldine Dawson,Maretha de Jonge,Richard Delorme,Irene Drmic,Eftichia Duketis,Frederico Duque,Annette Estes,Penny Farrar,Bridget A. Fernandez,Susan E. Folstein,Eric Fombonne,Christine M. Freitag,John Gilbert,Christopher Gillberg,Joseph T. Glessner,Jeremy Goldberg,Andrew Green,Jonathan Green,Stephen J. Guter,Hakon Hakonarson,Elizabeth A. Heron,Matthew Hill,Richard Holt,Jennifer L. Howe,Gillian Hughes,Vanessa Hus,Roberta Igliozzi,Cecilia Kim,Sabine M. Klauck,Alexander Kolevzon,Olena Korvatska,Vlad Kustanovich,Clara Lajonchere,Janine A. Lamb,Magdalena Laskawiec,Marion Leboyer,Ann Le Couteur,Bennett L. Leventhal,Anath C. Lionel,Anath C. Lionel,Xiao-Qing Liu,Catherine Lord,Linda Lotspeich,Sabata C. Lund,Elena Maestrini,William M. Mahoney,Carine Mantoulan,Christian R. Marshall,Helen McConachie,Christopher J. McDougle,Jane McGrath,William M. McMahon,Alison K. Merikangas,Ohsuke Migita,Nancy J. Minshew,Ghazala Mirza,Jeff Munson,Stanley F. Nelson,Carolyn Noakes,Abdul Noor,Gudrun Nygren,Guiomar Oliveira,Katerina Papanikolaou,Jeremy R. Parr,Barbara Parrini,Tara Paton,Andrew Pickles,Marion Pilorge,Joseph Piven,Chris P. Ponting,David J. Posey,Annemarie Poustka,Fritz Poustka,Aparna Prasad,Jiannis Ragoussis,Katy Renshaw,Jessica Rickaby,Wendy Roberts,Kathryn Roeder,Bernadette Rogé,Michael Rutter,Laura J. Bierut,John P. Rice,Jeff Salt,Katherine Sansom,Daisuke Sato,Ricardo Segurado,Ana Filipa Sequeira,Lili Senman,Lili Senman,Naisha Shah,Val C. Sheffield,Latha Soorya,Inês Sousa,Olaf Stein,Nuala Sykes,Vera Stoppioni,Christina Strawbridge,Raffaella Tancredi,Katherine E. Tansey,Bhooma Thiruvahindrapduram,Ann P. Thompson,Susanne Thomson,Ana Tryfon,John Tsiantis,Herman Van Engeland,John B. Vincent,Fred R. Volkmar,Simon Wallace,Kai Wang,Zhouzhi Wang,Thomas H. Wassink,Caleb Webber,Rosanna Weksberg,Kirsty Wing,Kerstin Wittemeyer,Shawn Wood,Jing Wu,Brian L. Yaspan,Danielle Zurawiecki,Lonnie Zwaigenbaum,Joseph D. Buxbaum,Rita M. Cantor,Edwin H. Cook,Hilary Coon,Michael L. Cuccaro,Bernie Devlin,Sean Ennis,Louise Gallagher,Daniel H. Geschwind,Michael Gill,Jonathan L. Haines,Joachim Hallmayer,Judith Miller,Anthony P. Monaco,John I. Nurnberger,Andrew D. Paterson,Margaret A. Pericak-Vance,Gerard D. Schellenberg,Peter Szatmari,Astrid M. Vicente,Veronica J. Vieland,Veronica J. Vieland,Ellen M. Wijsman,Stephen W. Scherer,James S. Sutcliffe,Catalina Betancur +181 more