Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome.
In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearran...
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2011-07-01
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doaj-5c43355a53914e768e4abdfa928036cf2020-11-25T01:04:30ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-07-0177e100217310.1371/journal.pgen.1002173Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome.Maria Clara BonagliaRoberto GiordaSilvana BeriCristina De AgostiniFrancesca NovaraMarco FicheraLucia GrilloOrnella GalesiAnnalisa VetroRoberto CicconeMaria Teresa BonatiSabrina GiglioRenzo GuerriniSara OsimaniSusan MarelliClaudio ZuccaRita GrassoRenato BorgattiElisa ManiCristina MottaMassimo MolteniCorrado RomanoDonatella GrecoSantina ReitanoAnna BaronciniElisabetta LapiAntonella CecconiGiulia ArrigoMaria Grazia PatricelliChiara PantaleoniStefano D'ArrigoDaria RivaFrancesca SciaccaBernardo Dalla BernardinaLeonardo ZoccanteFrancesca DarraCristiano TermineEmanuela MaseratiStefania BigoniEmanuela PrioloArmand BottaniStefania GimelliFrederique BenaAlfredo BruscoEleonora di GregorioIrene BagnascoUrsula GiussaniLucio NitschPierluigi PolitiMaria Luisa Martinez-FriasMaria Luisa Martínez-FernándezNieves Martínez GuardiaAnna BremerBritt-Marie AnderlidOrsetta ZuffardiIn this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17-74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS.http://europepmc.org/articles/PMC3136441?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Maria Clara Bonaglia Roberto Giorda Silvana Beri Cristina De Agostini Francesca Novara Marco Fichera Lucia Grillo Ornella Galesi Annalisa Vetro Roberto Ciccone Maria Teresa Bonati Sabrina Giglio Renzo Guerrini Sara Osimani Susan Marelli Claudio Zucca Rita Grasso Renato Borgatti Elisa Mani Cristina Motta Massimo Molteni Corrado Romano Donatella Greco Santina Reitano Anna Baroncini Elisabetta Lapi Antonella Cecconi Giulia Arrigo Maria Grazia Patricelli Chiara Pantaleoni Stefano D'Arrigo Daria Riva Francesca Sciacca Bernardo Dalla Bernardina Leonardo Zoccante Francesca Darra Cristiano Termine Emanuela Maserati Stefania Bigoni Emanuela Priolo Armand Bottani Stefania Gimelli Frederique Bena Alfredo Brusco Eleonora di Gregorio Irene Bagnasco Ursula Giussani Lucio Nitsch Pierluigi Politi Maria Luisa Martinez-Frias Maria Luisa Martínez-Fernández Nieves Martínez Guardia Anna Bremer Britt-Marie Anderlid Orsetta Zuffardi |
spellingShingle |
Maria Clara Bonaglia Roberto Giorda Silvana Beri Cristina De Agostini Francesca Novara Marco Fichera Lucia Grillo Ornella Galesi Annalisa Vetro Roberto Ciccone Maria Teresa Bonati Sabrina Giglio Renzo Guerrini Sara Osimani Susan Marelli Claudio Zucca Rita Grasso Renato Borgatti Elisa Mani Cristina Motta Massimo Molteni Corrado Romano Donatella Greco Santina Reitano Anna Baroncini Elisabetta Lapi Antonella Cecconi Giulia Arrigo Maria Grazia Patricelli Chiara Pantaleoni Stefano D'Arrigo Daria Riva Francesca Sciacca Bernardo Dalla Bernardina Leonardo Zoccante Francesca Darra Cristiano Termine Emanuela Maserati Stefania Bigoni Emanuela Priolo Armand Bottani Stefania Gimelli Frederique Bena Alfredo Brusco Eleonora di Gregorio Irene Bagnasco Ursula Giussani Lucio Nitsch Pierluigi Politi Maria Luisa Martinez-Frias Maria Luisa Martínez-Fernández Nieves Martínez Guardia Anna Bremer Britt-Marie Anderlid Orsetta Zuffardi Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome. PLoS Genetics |
author_facet |
Maria Clara Bonaglia Roberto Giorda Silvana Beri Cristina De Agostini Francesca Novara Marco Fichera Lucia Grillo Ornella Galesi Annalisa Vetro Roberto Ciccone Maria Teresa Bonati Sabrina Giglio Renzo Guerrini Sara Osimani Susan Marelli Claudio Zucca Rita Grasso Renato Borgatti Elisa Mani Cristina Motta Massimo Molteni Corrado Romano Donatella Greco Santina Reitano Anna Baroncini Elisabetta Lapi Antonella Cecconi Giulia Arrigo Maria Grazia Patricelli Chiara Pantaleoni Stefano D'Arrigo Daria Riva Francesca Sciacca Bernardo Dalla Bernardina Leonardo Zoccante Francesca Darra Cristiano Termine Emanuela Maserati Stefania Bigoni Emanuela Priolo Armand Bottani Stefania Gimelli Frederique Bena Alfredo Brusco Eleonora di Gregorio Irene Bagnasco Ursula Giussani Lucio Nitsch Pierluigi Politi Maria Luisa Martinez-Frias Maria Luisa Martínez-Fernández Nieves Martínez Guardia Anna Bremer Britt-Marie Anderlid Orsetta Zuffardi |
author_sort |
Maria Clara Bonaglia |
title |
Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome. |
title_short |
Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome. |
title_full |
Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome. |
title_fullStr |
Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome. |
title_full_unstemmed |
Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome. |
title_sort |
molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with phelan/mcdermid syndrome. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2011-07-01 |
description |
In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17-74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS. |
url |
http://europepmc.org/articles/PMC3136441?pdf=render |
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