Title
The SMAD-binding domain of SKI : a hotspot for de novo mutations causing Shprintzen-Goldberg syndrome The SMAD-binding domain of SKI : a hotspot for de novo mutations causing Shprintzen-Goldberg syndrome
Author
Faculty/Department
Faculty of Medicine and Health Sciences
Publication type
article
Publication
Leiden ,
Subject
Chemistry
Biology
Human medicine
Source (journal)
European journal of human genetics / European Society of Human Genetics. - Leiden
Volume/pages
23(2015) :2 , p. 224-228
ISSN
1018-4813
ISI
000347950200015
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
ShprintzenGoldberg 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 LoeysDietz 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.
Full text (open access)
https://repository.uantwerpen.be/docman/irua/116914/3598ebe7.pdf
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