@article{3087936,
    title = "The SMAD-binding domain of SKI: A hotspot for de novo mutations causing Shprintzen-Goldberg syndrome",
    author = "Schepers, D. and Doyle, A.J. and Oswald, G. and Sparks, E. and Myers, L. and Willems, P.J. and Mansour, S. and Simpson, M.A. and Frysira, H. and Maat-Kievit, A. and Van Minkelen, R. and Hoogeboom, J.M. and Mortier, G.R. and Titheradge, H. and Brueton, L. and Starr, L. and Stark, Z. and Ockeloen, C. and Lourenco, C.M. and Blair, E. and Hobson, E. and Hurst, J. and Maystadt, I. and Destrée, A. and Girisha, K.M. and Miller, M. and Dietz, H.C. and Loeys, B. and Van Laer, L.",
    journal = "European Journal of Human Genetics: EJHG",
    year = "2015",
    volume = "23",
    number = "2",
    pages = "224-228",
    publisher = "Nature Publishing Group",
    issn = "1018-4813, 1476-5438",
    doi = "10.1038/ejhg.2014.61",
    keywords = "Smad protein;  transforming growth factor beta;  DNA binding protein;  oncoprotein;  protein binding;  SKI protein, human;  Smad protein, adolescent;  adult;  Article;  child;  clinical article;  controlled study;  female;  galactosialidosis;  gene;  heterozygote;  human;  male;  middle aged;  missense mutation;  mosaicism;  next generation sequencing;  pathogenesis;  preschool child;  priority journal;  protein binding;  protein domain;  protein localization;  school child;  shprintzen goldberg syndrome;  sibling;  ski gene;  young adult;  arachnodactyly;  binding site;  chemistry;  Craniosynostoses;  exon;  genetics;  Marfan syndrome;  metabolism, Adolescent;  Adult;  Arachnodactyly;  Binding Sites;  Child;  Child, Preschool;  Craniosynostoses;  DNA-Binding Proteins;  Exons;  Female;  Humans;  Male;  Marfan Syndrome;  Middle Aged;  Mutation, Missense;  Protein Binding;  Proto-Oncogene Proteins;  Smad Proteins",
    abstract = "Shprintzen-Goldberg syndrome (SGS) is a rare, systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations that show a significant overlap with the features observed in the Marfan (MFS) and Loeys-Dietz syndrome (LDS). A distinguishing observation in SGS patients is the presence of intellectual disability, although not all patients in this series present this finding. Recently, SGS was shown to be due to mutations in the SKI gene, encoding the oncoprotein SKI, a repressor of TGFβ activity. Here, we report eight recurrent and three novel SKI mutations in eleven SGS patients. All were heterozygous missense mutations located in the R-SMAD binding domain, except for one novel in-frame deletion affecting the DHD domain. Adding our new findings to the existing data clearly reveals a mutational hotspot, with 73% (24 out of 33) of the hitherto described unrelated patients having mutations in a stretch of five SKI residues (from p.(Ser31) to p.(Pro35)). This implicates that the initial molecular testing could be focused on mutation analysis of the first half of exon 1 of SKI. As the majority of the known mutations are located in the R-SMAD binding domain of SKI, our study further emphasizes the importance of TGFβ signaling in the pathogenesis of SGS. © 2015 Macmillan Publishers Limited All rights reserved."
}