The SMAD-binding domain of SKI: A hotspot for de novo mutations causing Shprintzen-Goldberg syndrome

Dorien Schepers, Alexander J. Doyle, Gretchen Oswald, Elizabeth Sparks, Loretha Myers, Patrick J. Willems, Sahar Mansour, Michael A. Simpson, Helena Frysira, Anneke Maat-Kievit, Rick Van Minkelen, Jeanette M. Hoogeboom, Geert R. Mortier, Hannah Titheradge, Louise Brueton, Lois Starr, Zornitza Stark, Charlotte Ockeloen, Charles Marques Lourenco, Ed BlairEmma Hobson, Jane Hurst, Isabelle Maystadt, Anne Destrée, Katta M. Girisha, Michelle Miller, Harry C. Dietz, Bart Loeys, Lut Van Laer

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)224-228
Number of pages5
JournalEuropean Journal of Human Genetics
Issue number2
StatePublished - Feb 20 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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