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RESEARCH PRODUCT
In-Frame Mutations in Exon 1 of SKI Cause Dominant Shprintzen-Goldberg Syndrome
Anne H. ChildChristophe BéroudCatherine BoileauJaime Sanchez Del PozoJulie De BackerCyril GoizetJeanne AmielLesley C. AdèsLesley C. AdèsPierre VabresAnne De PaepeJulien ThevenonLaurence DuplombKatherine HolmanKatherine HolmanChristel Thauvin-robinetClarisse BaumannFrédéric HuetGhislaine PlessisGwenaëlle Collod-béroudBert CallewaertEloisa ArbustiniHenri PlauchuBernard AralPeter N. RobinsonSophie JuliaJean Baptiste RivièreValérie Cormier-daireGavin ArnoNadège GigotMarjolijn RenardLucie GueneauGuillaume JondeauPatrick CallierJean Benoît CourcetMaja Di RoccoLaurence FaivreVirginie CarmignacEstelle LopezMaurizia Grassosubject
MaleModels Molecularmedicine.disease_cause[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biologyMarfan SyndromeArachnodactylyExon0302 clinical medicineGene OrderMissense mutationGenetics(clinical)Child[ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human geneticsGenetics (clinical)Exome sequencingGenes DominantGenetics0303 health sciencesMutationShprintzen–Goldberg syndromeExonsPhenotypePedigreeDNA-Binding ProteinsPhenotypeChild PreschoolFemalemedicine.symptomAdultAdolescentMolecular Sequence Data[ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biologyBiology[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics03 medical and health sciencesCamptodactylyCraniosynostosesYoung Adultstomatognathic systemReportProto-Oncogene ProteinsmedicineGeneticsHumansAmino Acid Sequence030304 developmental biologyFacies[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biologymedicine.diseaseMolecular biologyProtein Structure TertiaryArachnodactyly[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human geneticsMutationSequence Alignmenthuman activities030217 neurology & neurosurgerydescription
International audience; Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. Using family-based exome sequencing, we identified a dominantly inherited heterozygous in-frame deletion in exon 1 of SKI. Direct sequencing of SKI further identified one overlapping heterozygous in-frame deletion and ten heterozygous missense mutations affecting recurrent residues in 18 of the 19 individuals screened for SGS; these individuals included one family affected by somatic mosaicism. All mutations were located in a restricted area of exon 1, within the R-SMAD binding domain of SKI. No mutation was found in a cohort of 11 individuals with other marfanoid-craniosynostosis phenotypes. The interaction between SKI and Smad2/3 and Smad 4 regulates TGF-β signaling, and the pattern of anomalies in Ski-deficient mice corresponds to the clinical manifestations of SGS. These findings define SGS as a member of the family of diseases associated with the TGF-β-signaling pathway.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2012-11-01 |