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 TGFb 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 TGFb signaling in the pathogenesis of SGS.

Identification of a New Candidate Locus for Ebstein Anomaly in 1p36.2

“…2 ). Patients with heterozygous missense mutations and in-frame deletions in SKI show a multisystemic connective tissue disorder, called ShprintzenGoldberg syndrome, characterized by a marfanoid habitus, craniosynostosis, severe skeletal muscle hypotonia, intellectual disability, and cardiovascular abnormalities such as mitral valve prolapse and aortic dilation [Carmignac et al, 2012;Schepers et al, 2015]. The proximal CR is delimited by the deletion reported here.…”

Navigating the Phenotype Frontier: The Monarch Initiative

“…For instance, we could speculate that mutation in the human SKI gene might lead to a disease with similarities to Marfan syndrome and Loeys-Dietz syndrome. In fact, these considerations supported the discovery of mutations in the SKI gene as the cause of Shprintzen-Goldberg syndrome (Schepers et al 2015). Additional biological complexities make it even harder to build a complete and accurate picture with the available phenotypic information.…”

Navigating the phenotype frontier: The Monarch Initiative

“…For instance, we could speculate that mutation in the human SKI gene might lead to a disease with similarities to Marfan syndrome and Loeys-Dietz syndrome. In fact, these considerations supported the discovery of mutations in the SKI gene as the cause of Shprintzen Goldberg syndrome (Schepers et al 2015).…”