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Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies
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نویسنده
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acuna-hidalgo r. ,deriziotis p. ,steehouwer m. ,gilissen c. ,graham s.a. ,van dam s. ,hoover-fong j. ,telegrafi a.b. ,destree a. ,smigiel r. ,lambie l.a. ,kayserili h. ,altunoglu u. ,lapi e. ,uzielli m.l. ,aracena m. ,nur b.g. ,mihci e. ,moreira l.m.a. ,borges ferreira v. ,horovitz d.d.g. ,da rocha k.m. ,jezela-stanek a. ,brooks a.s. ,reutter h. ,cohen j.s. ,fatemi a. ,smitka m. ,grebe t.a. ,di donato n. ,deshpande c. ,vandersteen a. ,marques lourenço c. ,dufke a. ,rossier e. ,andre g. ,baumer a. ,spencer c. ,mcgaughran j. ,franke l. ,veltman j.a. ,de vries b.b.a. ,schinzel a. ,fisher s.e. ,hoischen a. ,van bon b.w.
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منبع
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plos genetics - 2017 - دوره : 13 - شماره : 3
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چکیده
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Schinzel-giedion syndrome (sgs) is a rare developmental disorder characterized by multiple malformations,severe neurological alterations and increased risk of malignancy. sgs is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of setbp1. mutations in this hotspot disrupt a degron,a signal for the regulation of protein degradation,and lead to the accumulation of setbp1 protein. overlapping setbp1 hotspot mutations have been observed recurrently as somatic events in leukemia. we collected clinical information of 47 sgs patients (including 26 novel cases) with germline setbp1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the setbp1 hotspot. different mutations within and around the setbp1 hotspot have varying effects on setbp1 stability and protein levels in vitro and in in silico modeling. substitutions in setbp1 residue i871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in sgs than in leukemia. on the other hand,substitutions in residue d868 lead to the largest increase in protein levels. individuals with germline mutations affecting d868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline setbp1 mutations. our findings substantiate that,despite their overlap,somatic setbp1 mutations driving malignancy are more disruptive to the degron than germline setbp1 mutations causing sgs. additionally,this suggests that the functional threshold for the development of cancer driven by the disruption of the setbp1 degron is higher than for the alteration in prenatal development in sgs. drawing on previous studies of somatic setbp1 mutations in leukemia,our results reveal a genotype-phenotype correlation in germline setbp1 mutations spanning a molecular,cellular and clinical phenotype. © 2017 acuna-hidalgo et al.
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آدرس
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department of human genetics,radboud institute of molecular life sciences,radboud university medical center,nijmegen, Netherlands, language and genetics department,max planck institute for psycholinguistics,nijmegen, Netherlands, department of human genetics,radboud institute of molecular life sciences,radboud university medical center,nijmegen, Netherlands, department of human genetics,radboud institute of molecular life sciences,radboud university medical center,nijmegen,netherlands,department of human genetics,donders centre for neuroscience,radboud university medical center,nijmegen, Netherlands, language and genetics department,max planck institute for psycholinguistics,nijmegen, Netherlands, university of groningen,university medical center groningen,department of genetics,groningen, Netherlands, mckusick-nathans institute of genetic medicine,johns hopkins university,baltimore,md, United States, genedx,gaithersburg,md, United States, institute of pathology and genetics (ipg),gosselies, Belgium, department of pediatrics and rare disorders,medical university,wroclaw, Poland, division of human genetics,national health laboratory service and school of pathology,faculty of health sciences,university of the witwatersrand,johannesburg, South Africa, medical genetics department,koç university school of medicine (kusom),istanbul, Turkey, medical genetics department,istanbul medical faculty,istanbul university,istanbul, Turkey, medical genetics unit,anna meyer children's university hospital,florence, Italy, university of florence,genetic science,firenze, Italy, división de pediatría,pontificia universidad católica de chile and unidad de genética,hospital dr. luis calvo mackenna,santiago, Chile, department of pediatric genetics,akdeniz university medical school,antalya, Turkey, department of pediatric genetics,akdeniz university medical school,antalya, Turkey, laboratory of human genetics,biology institute,federal university of bahia (ufba),bahia, Brazil, hospital santa izabel,salvador-bahia, Brazil, ceres-genetica reference center and studies in medical genetics and instituto fernandes figueira / fiocruz,rio de janeiro, Brazil, center for human genome studies,institute of biosciences,usp,sao paulo, Brazil, department of medical genetics,children’s memorial health institute,warsaw, Poland, department of clinical genetics,sophia children's hospital,erasmus mc,rotterdam, Netherlands, institute of human genetics,university of bonn,bonn,germany,department of neonatology and pediatric intensive care,children's hospital,university of bonn,bonn, Germany, division of neurogenetics,kennedy krieger institute,departments of neurology and pediatrics,the johns hopkins hospital,baltimore,md, United States, division of neurogenetics,kennedy krieger institute,departments of neurology and pediatrics,the johns hopkins hospital,baltimore,md, United States, abteilung neuropädiatrie,medizinische fakultät carl gustav carus,technische universität dresden, Germany, division of genetics & metabolism,phoenix children’s hospital,phoenix,az, United States, institute for clinical genetics,tu dresden,dresden, Germany, department of genetics,guy's and st. thomas' nhs foundation trust,london, United Kingdom, north west thames regional genetics unit,kennedy galton centre,north west london hospitals nhs trust,northwick park & st marks hospital,harrow,middlesex, United Kingdom, neurogenetics unit,department of medical genetics school of medicine of ribeirao preto,university of sao paulo,sao paulo, Brazil, institute of medical genetics and applied genomics,university of tübingen,tübingen, Germany, institute of medical genetics and applied genomics,university of tübingen,tübingen, Germany, unité de foetopathologie,hôpital pellegrin,place amélie raba léon,bordeaux, France, institute of medical genetics,university of zurich,schlieren, Switzerland, division of human genetics,national health laboratory service and school of pathology,faculty of health sciences,university of the witwatersrand,johannesburg, South Africa, genetic health queensland,royal brisbane and women's hospital,brisbane,qld,australia,school of medicine,the university of queensland,brisbane,qld, Australia, university of groningen,university medical center groningen,department of genetics,groningen, Netherlands, department of human genetics,donders centre for neuroscience,radboud university medical center,nijmegen,netherlands,institute of genetic medicine,international centre for life,newcastle university,newcastle upon tyne, United Kingdom, department of human genetics,radboud institute of molecular life sciences,radboud university medical center,nijmegen,netherlands,department of human genetics,donders centre for neuroscience,radboud university medical center,nijmegen, Netherlands, institute of medical genetics,university of zurich,schlieren, Switzerland, language and genetics department,max planck institute for psycholinguistics,nijmegen,netherlands,donders institute for brain,cognition and behaviour,radboud university,nijmegen, Netherlands, department of human genetics,radboud institute of molecular life sciences,radboud university medical center,nijmegen,netherlands,department of human genetics,donders centre for neuroscience,radboud university medical center,nijmegen,netherlands,department of internal medicine and radboud center for infectious diseases (rci),radboud university medical center,nijmegen, Netherlands, department of human genetics,radboud institute of molecular life sciences,radboud university medical center,nijmegen, Netherlands
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