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Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with phelan/mcdermid syndrome
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نویسنده
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bonaglia m.c. ,giorda r. ,beri s. ,de agostini c. ,novara f. ,fichera m. ,grillo l. ,galesi o. ,vetro a. ,ciccone r. ,bonati m.t. ,giglio s. ,guerrini r. ,osimani s. ,marelli s. ,zucca c. ,grasso r. ,borgatti r. ,mani e. ,motta c. ,molteni m. ,romano c. ,greco d. ,reitano s. ,baroncini a. ,lapi e. ,cecconi a. ,arrigo g. ,patricelli m.g. ,pantaleoni c. ,d'arrigo s. ,riva d. ,sciacca f. ,bernardina d.b. ,zoccante l. ,darra f. ,termine c. ,maserati e. ,bigoni s. ,priolo e. ,bottani a. ,gimelli s. ,bena f. ,brusco a. ,gregorio e. ,bagnasco i. ,giussani u. ,nitsch l. ,politi p. ,martinez-frias m.l. ,martínez-fernández m.l. ,guardia n. ,bremer a. ,anderlid b.-m. ,zuffardi o.
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منبع
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plos genetics - 2011 - دوره : 7 - شماره : 7
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چکیده
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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. © 2011 bonaglia et al.
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آدرس
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cytogenetics laboratory,scientific institute e. medea,bosisio parini, Italy, molecular biology laboratory,scientific institute e. medea,bosisio parini, Italy, molecular biology laboratory,scientific institute e. medea,bosisio parini, Italy, cytogenetics laboratory,scientific institute e. medea,bosisio parini, Italy, biologia generale e genetica medica,università di pavia,pavia, Italy, laboratorio di diagnosi genetica,istituto scientifico oasi maria santissima,troina, Italy, laboratorio di diagnosi genetica,istituto scientifico oasi maria santissima,troina, Italy, laboratorio di diagnosi genetica,istituto scientifico oasi maria santissima,troina, Italy, biologia generale e genetica medica,università di pavia,pavia, Italy, biologia generale e genetica medica,università di pavia,pavia, Italy, clinic of medical genetics,irccs auxologico italiano,milano, Italy, medical genetics section,department of clinical pathophysiology,university of florence,firenze,italy,medical genetics unit,meyer children's university hospital,firenze, Italy, pediatric neurology unit,children's hospital a. meyer,university of florence,firenze, Italy, biologia molecolare e citogenetica,diagnostica e ricerca,ospedale san raffaele,milano, Italy, department of child neuropsychiatry and neurorehabilitation 1,scientific institute e. medea,bosisio parini, Italy, neurofisiologia clinica,scientific institute e. medea,bosisio parini, Italy, department of child neuropsychiatry and neurorehabilitation 1,scientific institute e. medea,bosisio parini, Italy, department of child neuropsychiatry and neurorehabilitation 1,scientific institute e. medea,bosisio parini, Italy, department of child psychopathology,scientific institute e. medea,bosisio parini, Italy, department of child psychopathology,scientific institute e. medea,bosisio parini, Italy, department of child psychopathology,scientific institute e. medea,bosisio parini, Italy, unità operativa di pediatria e genetica medica,irccs oasi maria santissima troina, Italy, unità operativa di pediatria e genetica medica,irccs oasi maria santissima troina, Italy, unità operativa di pediatria e genetica medica,irccs oasi maria santissima troina, Italy, unità operativa di genetica medica,dipartimento materno-infantile ausl imola,imola, Italy, medical genetics unit,meyer children's university hospital,firenze,italy,genetics and molecular medicine unit,university of florence,firenze, Italy, unità operativa di pediatria e neonatologia,ambulatorio di genetica clinica,ospedale s. maria annunziata,firenze, Italy, biologia generale e genetica medica,università di pavia,pavia, Italy, biologia molecolare e citogenetica,diagnostica e ricerca,ospedale san raffaele,milano, Italy, developmental neurology unit,carlo besta foundation neurological institute,milano, Italy, developmental neurology unit,carlo besta foundation neurological institute,milano, Italy, developmental neurology unit,carlo besta foundation neurological institute,milano, Italy, laboratorio di patologia clinica e genetica medica,servizio di citogenetica,carlo besta foundation neurological institute,milano, Italy, unità operativa complessa neuropsichiatria infantile,azienda ospedaliera universitaria integrata policlinico g.b. rossi,verona, Italy, unità operativa complessa neuropsichiatria infantile,azienda ospedaliera universitaria integrata policlinico g.b. rossi,verona, Italy, unità operativa complessa neuropsichiatria infantile,azienda ospedaliera universitaria integrata policlinico g.b. rossi,verona, Italy, child neuropsychiatry unit,department of experimental medicine,university of insubria,varese, Italy, biologia e genetica,dipartimento di scienze biomediche sperimentali e cliniche,università dell'lnsubria,varese, Italy, medical genetic section,department of experimental and diagnostic medicine,university of ferrara,ferrara, Italy, unità operativa complessa genetica medica,azienda ospedaliera bbm,reggio calabria, Italy, service de médecine génétique,département de médecine génétique et de laboratoire,höpital cantonal de genève,geneva, Switzerland, service de médecine génétique,département de médecine génétique et de laboratoire,höpital cantonal de genève,geneva, Switzerland, service de médecine génétique,département de médecine génétique et de laboratoire,höpital cantonal de genève,geneva, Switzerland, department of genetics,biology and biochemistry,university of torino,torino, Italy, department of genetics,biology and biochemistry,university of torino,torino, Italy, struttura complessa npi ospedale martini,torino, Italy, laboratorio di genetica medica,ospedali riuniti di bergamo,bergamo, Italy, department of cellular and molecular biology and pathology,federico ii university,napoli, Italy, department of health sciences,university of pavia,pavia, Italy, facultad de medicina,universidad complutense de madrid,madrid,spain,centro de investigación sobre anomalías congénitas (ciac),instituto de salud carlos iii,madrid, Spain, facultad de medicina,universidad complutense de madrid,madrid,spain,centro de investigación sobre anomalías congénitas (ciac),instituto de salud carlos iii,madrid,spain,centro de investigación biomédica en red de enfermedades raras (ciberer),madrid, Spain, servicio de neonatología,hospital severo ochoa leganes,madrid, Spain, department of molecular medicine and surgery,karolinska institute,stockholm, Sweden, department of molecular medicine and surgery,karolinska institute,stockholm, Sweden, biologia generale e genetica medica,università di pavia,pavia,italy,fondazione irccs c. mondino,pavia, Italy
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