title: The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen-Goldberg syndrome.
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.
authors.affiliation: Center for Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Dorien
authors.identifier: 0000000342256621
authors.initials: D
authors.lastname: Schepers
authors.affiliation: 1] McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA [2] Howard Hughes Medical Institute, Baltimore, MD, USA.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Doyle
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Oswald
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sparks
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Loretha
authors.initials: L
authors.lastname: Myers
authors.affiliation: GENDIA, GENetic DIAgnostic Network, Antwerp, Belgium.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Willems
authors.affiliation: SW Thames Regional Genetics Service, St George's, University of London, London, UK.
authors.forename: Sahar
authors.initials: S
authors.lastname: Mansour
authors.affiliation: Division of Genetics and Molecular Medicine, Department of Medical and Molecular Genetics, King's College London School of Medicine, London, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Simpson
authors.affiliation: Department of Medical Genetics, National and Kapodistrian University of Athens Medical School, Athens, Greece.
authors.forename: Helena
authors.initials: H
authors.lastname: Frysira
authors.affiliation: Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors.forename: Anneke
authors.initials: A
authors.lastname: Maat-Kievit
authors.affiliation: Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Van Minkelen
authors.affiliation: Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: Hoogeboom
authors.affiliation: Center for Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Geert R
authors.initials: GR
authors.lastname: Mortier
authors.affiliation: Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Titheradge
authors.affiliation: Department of Clinical Genetics, Birmingham Women's Hospital, Birmingham, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Brueton
authors.affiliation: Clinical Genetics, Munroe-Meyer Institute for Genetics and Rehabilitation, Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Lois
authors.initials: L
authors.lastname: Starr
authors.affiliation: Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors.forename: Zornitza
authors.initials: Z
authors.lastname: Stark
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ockeloen
authors.affiliation: Department of Medical Genetics, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Charles Marques
authors.initials: CM
authors.lastname: Lourenco
authors.affiliation: Department of Clinical Genetics, Churchill Hospital, Oxford, UK.
authors.forename: Ed
authors.initials: E
authors.lastname: Blair
authors.affiliation: Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Hobson
authors.affiliation: Department of Clinical Genetics, Great Ormond Street Hospital, London, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Hurst
authors.affiliation: Center for Human Genetics, Institute for Pathology and Genetics (IPG), Gosselies, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maystadt
authors.affiliation: Center for Human Genetics, Institute for Pathology and Genetics (IPG), Gosselies, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Destrée
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Kasturba Medical College, Manipal University, Manipal, India.
authors.forename: Katta M
authors.initials: KM
authors.lastname: Girisha
authors.affiliation: Department of Cardiology, All Childrens Hospital, St. Petersburg, FL, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Miller
authors.affiliation: 1] McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA [2] Howard Hughes Medical Institute, Baltimore, MD, USA.
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dietz
authors.affiliation: Center for Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Loeys
authors.affiliation: Center for Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
authors.forename: Lut
authors.initials: L
authors.lastname: Van Laer
mesh_terms: D000293:Adolescent; D000328:Adult; D054119:Arachnodactyly / Q000175:diagnosis / Q000235:genetics*; D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D003398:Craniosynostoses / Q000175:diagnosis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000175:diagnosis / Q000235:genetics*; D008875:Middle Aged; D020125:Mutation, Missense; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D051785:Smad Proteins; C060614:SKI protein, human
references.citation: J Biol Chem. 1999 Dec 3;274(49):35269-77
references.pmid: 10575014
references.citation: Mech Dev. 2000 Jul;95(1-2):147-62
references.pmid: 10906458
references.citation: Nat Genet. 2011 Feb;43(2):121-6
references.pmid: 21217753
references.citation: Nat Genet. 2006 Apr;38(4):452-7
references.pmid: 16550171
references.citation: Cell Res. 2009 Jan;19(1):47-57
references.pmid: 19114989
references.citation: Eur J Hum Genet. 2010 Aug;18(8):895-901
references.pmid: 20389311
references.citation: Genes Dev. 1999 Sep 1;13(17):2196-206
references.pmid: 10485843
references.citation: Nat Genet. 2012 Nov;44(11):1249-54
references.pmid: 23023332
references.citation: Am J Hum Genet. 2012 Nov 2;91(5):950-7
references.pmid: 23103230
references.citation: Science. 2006 Apr 7;312(5770):117-21
references.pmid: 16601194
references.citation: J Craniofac Genet Dev Biol. 1982;2(1):65-74
references.pmid: 6182156
references.citation: Dev Biol. 1997 Dec 15;192(2):392-404
references.pmid: 9441676
references.citation: Science. 2011 Apr 15;332(6027):358-61
references.pmid: 21493862
references.citation: J Clin Invest. 2004 Dec;114(11):1586-92
references.pmid: 15546004
references.citation: Am J Med Genet A. 2005 Jun 15;135(3):251-62
references.pmid: 15884042
references.citation: Nat Genet. 2003 Mar;33(3):407-11
references.pmid: 12598898
references.citation: Am J Med Genet A. 2014 Mar;164A(3):676-84
references.pmid: 24357594
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):5924-9
references.pmid: 10811875
references.citation: Genes Dev. 1997 Aug 15;11(16):2029-39
references.pmid: 9284043
references.citation: Genes Dev. 1999 Feb 15;13(4):412-23
references.pmid: 10049357