6533b7d2fe1ef96bd125f5a0
RESEARCH PRODUCT
Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction
Antonio VitobelloChristel DepienneKelly RadtkeBruria Ben-zeevVaidutis KučinskasHirofumi KashiiLeslie GrangerFlorence DemurgerAdi Vaknin-dembinskyAndrou WaheebTakeshi MizuguchiLip H. MoeyUrania KotzaeridouFrédérique BénaFernando KokTimothy Blake PalculictYasmin Hamzavi AbediSatoko MiyatakeAnne-sophie Denommé-pichonLinda ManwaringLaura Elena OrecLaurens WielHan G. BrunnerHan G. BrunnerSylvie OdentEric VilainLinh TranSimon E. FisherSimon E. FisherEmmanuèlle C. DélotVidya KrishnamurthyRebecca C. SpillmannHilary CoonShelagh JossHui B. ChewMatias WagnerDavid A. DymentKirsty McwalterMichael W. ParkerAdam JacksonMargje SinnemaPengfei LiuPengfei LiuElke De BoerAlma KuechlerChristoffer NellåkerChristoffer NellåkerChristian GilissenYasuo HachiyaMarcia C. WillingShivarajan M. AmudhavalliShivarajan M. AmudhavalliAlexander P.a. StegmannAnge-line BruelSiddharth BankaSiddharth BankaJoery Den HoedVardiella MeinerRosalyn JewellBritton D ZuccarelliAlexander J. M. DingemansKelly L. JonesKelly L. JonesAnja A. Kattentidt-mouravievaMatthew OsmondOrly ElpelegAndrea K. PetersenNicolas GuexDianne F. NewburyJill A. RosenfeldAlexandre ReymondMohamad A. MikatiTjitske KleefstraLisenka E.l.m. VissersNaomichi MatsumotoVincent R. BonaguraVincent R. BonaguraLoreta CimbalistienėBenoît MazelHayley S. MountfordIsabelle ThiffaultIsabelle ThiffaultRolph PfundtRuth Newbury-ecobTeresa Santiago-simAlinoë LavillaureixEglė PreikšaitienėJacqueline ChrastToshiyuki ItaiNorine VoisinUsha KiniEmmanuelle RanzaCaitlin SchwagerCaitlin SchwagerBrooke HoristSamantha A. Schrier VerganoJennifer HanebeckJuliana H. Vedovato-dos-santosMitsuhiro KatoTheresa BrunetLot Snijders BlokLot Snijders BlokJayne Y. Hehir-kwaShehla MohammedBenjamin HaberHagar Mor-shakedLaurence FaivreDian DonnaiDian Donnaisubject
0301 basic medicineMaleModels MolecularMISSENSE MUTATIONSCHROMATINTranscription GeneticCellMedizinDiseaseHaploinsufficiencymedicine.disease_cause0302 clinical medicineMissense mutationde novo variantsGenetics (clinical)INTERLEUKIN-2seizuresGenetics0303 health sciencesMutationChromatin bindingneurodevelopmental disordersMetabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6]SATB1Phenotypemedicine.anatomical_structureintellectual disabilityFemaleHaploinsufficiencyteeth abnormalitiesProtein BindingNeuroinformaticsEXPRESSIONGENESMutation MissenseBiologyBINDING PROTEINREGION03 medical and health sciencesSATB1Protein DomainsReportGeneticsmedicineHPO-based analysisHumansGenetic Association StudiesHpo-based Analysis ; Satb1 ; Cell-based Functional Assays ; De Novo Variants ; Intellectual Disability ; Neurodevelopmental Disorders ; Seizures ; Teeth Abnormalities030304 developmental biology[SDV.GEN]Life Sciences [q-bio]/GeneticsNeurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]Matrix Attachment Region Binding Proteins030104 developmental biologyNeurodevelopmental DisordersMutationNanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19]030217 neurology & neurosurgerycell-based functional assaysdescription
AbstractWhereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene,SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carryingSATB1variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. Contrastingly, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay and encode truncated proteins, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-02-04 |