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.

Figure 1

Clinical pictures of SGS patients. Note typical craniofacial features including craniosynostotic skull with proptosis, dolichocephaly with retrognathia, low set ears, and hypertelorism. Skeletal findings include arachnodactyly, scoliosis, and a combination of joint hyperlaxity and contractures with camptodactyly.

Figure 2

(a) Schematic representation of the SKI domains in exon 1. Location of all SKI mutations known so far with respect to the binding sites of SKI-binding partners. Mutations in red are identified and discussed in this paper. (b) Overview of all published mutations identified so far in SKI. *One patient was identical in Doyle et al (patient 4) and Carmignac et al (patient 12), resulting in 33 independent SGS patients with a mutation in SKI. A full color version of this figure is available at the European Journal of Human Genetics journal online.