Schepers Dorien, Doyle Alexander J, Oswald Gretchen, Sparks Elizabeth, Myers Loretha, Willems Patrick J, Mansour Sahar, Simpson Michael A, Frysira Helena, Maat-Kievit Anneke, Van Minkelen Rick, Hoogeboom Jeanette M, Mortier Geert R, Titheradge Hannah, Brueton Louise, Starr Lois, Stark Zornitza, Ockeloen Charlotte, Lourenco Charles Marques, Blair Ed, Hobson Emma, Hurst Jane, Maystadt Isabelle, Destrée Anne, Girisha Katta M, Miller Michelle, Dietz Harry C, Loeys Bart, Van Laer Lut
Center for Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
1] McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA [2] Howard Hughes Medical Institute, Baltimore, MD, USA.
Eur J Hum Genet. 2015 Feb;23(2):224-8. doi: 10.1038/ejhg.2014.61. Epub 2014 Apr 16.
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.
施普林曾-戈德堡综合征（SGS）是一种罕见的全身性结缔组织疾病，其特征为颅面、骨骼和心血管方面的表现，这些表现与马凡综合征（MFS）和洛伊迪茨综合征（LDS）中观察到的特征有显著重叠。SGS患者的一个显著特征是存在智力障碍，尽管本系列中的并非所有患者都有这一表现。最近研究表明，SGS是由SKI基因突变所致，该基因编码癌蛋白SKI，一种TGFβ活性的抑制因子。在此，我们报告了11例SGS患者中的8个复发性SKI突变和3个新的SKI突变。除了一个影响DHD结构域的新的框内缺失外，所有突变均为位于R-SMAD结合结构域的杂合错义突变。将我们的新发现与现有数据相结合，清楚地揭示了一个突变热点，迄今为止所描述的无关患者中有73%（33例中的24例）在SKI的五个连续残基（从p.(Ser31)到p.(Pro35)）处发生突变。这意味着最初的分子检测可以集中在SKI外显子1前半部分的突变分析上。由于大多数已知突变位于SKI的R-SMAD结合结构域，我们的研究进一步强调了TGFβ信号通路在SGS发病机制中的重要性。
