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Eur J Hum Genet. 2015 Feb;23(2):224-8. doi: 10.1038/ejhg.2014.61. Epub 2014 Apr 16.

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

Author information

1
Center for Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
2
1] McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA [2] Howard Hughes Medical Institute, Baltimore, MD, USA.
3
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4
GENDIA, GENetic DIAgnostic Network, Antwerp, Belgium.
5
SW Thames Regional Genetics Service, St George's, University of London, London, UK.
6
Division of Genetics and Molecular Medicine, Department of Medical and Molecular Genetics, King's College London School of Medicine, London, UK.
7
Department of Medical Genetics, National and Kapodistrian University of Athens Medical School, Athens, Greece.
8
Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
9
Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham, UK.
10
Clinical Genetics, Munroe-Meyer Institute for Genetics and Rehabilitation, Nebraska Medical Center, Omaha, NE, USA.
11
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
12
Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
13
Department of Medical Genetics, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
14
Department of Clinical Genetics, Churchill Hospital, Oxford, UK.
15
Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.
16
Department of Clinical Genetics, Great Ormond Street Hospital, London, UK.
17
Center for Human Genetics, Institute for Pathology and Genetics (IPG), Gosselies, Belgium.
18
Division of Medical Genetics, Department of Pediatrics, Kasturba Medical College, Manipal University, Manipal, India.
19
Department of Cardiology, All Childrens Hospital, St. Petersburg, FL, USA.

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.

PMID:
24736733
PMCID:
PMC4297897
DOI:
10.1038/ejhg.2014.61
[Indexed for MEDLINE]
Free PMC Article
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