In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome

Abstract

Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. Using family-based exome sequencing, we identified a dominantly inherited heterozygous in-frame deletion in exon 1 of SKI. Direct sequencing of SKI further identified one overlapping heterozygous in-frame deletion and ten heterozygous missense mutations affecting recurrent residues in 18 of the 19 individuals screened for SGS; these individuals included one family affected by somatic mosaicism. All mutations were located in a restricted area of exon 1, within the R-SMAD binding domain of SKI. No mutation was found in a cohort of 11 individuals with other marfanoid-craniosynostosis phenotypes. The interaction between SKI and Smad2/3 and Smad 4 regulates TGF-β signaling, and the pattern of anomalies in Ski-deficient mice corresponds to the clinical manifestations of SGS. These findings define SGS as a member of the family of diseases associated with the TGF-β-signaling pathway.

Figure 1

Clinical Presentations and Pedigrees of Subjects with SGS and Mutations in SKI (A) Photographs of affected individual II-1 (from family 2), who has a SKI de novo c.94C>G variant. Note the hypertelorism, proptosis, downslanting palpebral fissures, maxillary and mandibular hypoplasia, low-set ears (Aa–Ac), joint contractures (Ad), arachnodactyly and camptodactyly (Ae), deformed feet (Af–Ag), severe scoliosis (Ah), translucent skin (Ai), and hypertrophy of the palatal shelves (Aj). (B) Photographs of affected individual 14 (family 8), who has a SKI de novo c.103C>T variant. Note the dysmorphic features in favor of SGS (Ba–Bb), severe pectus carinatum (Bc), arachnodactyly, and camptodactyly (Bd). (C) Photographs of affected individual III-4 (from family 3), who has a c.280_291delTCCGACCGCTCC variant in exon 1 of SKI. Note the dysmorphic features and habitus in favor of SGS (Ca, Cc, and Cd), foot deformity (Cb), and hand deformity with camptodactyly (Ce). (D) Photographs of affected individual IV-2 from family 3 (child of individual III-4 in C). (E) Pedigrees of families 1 (F1), 2 (F2), 3 (F3), and 4 (F4) studied by exome sequencing. Individuals studied are shown by an arrow.

Figure 2

Location of SGS-Associated Mutations in SKI (A) Schematic representation of the seven coding exons of SKI (top). The 5′ and 3′ UTRs are denoted in light gray. Exon 1 encodes the N-terminal R-SMAD- and SMAD- binding domains (blue and red box, respectively, at the bottom) and the DHD domain (purple box), and the remaining exons encode the C terminus with its two coiled-coil domains (green boxes at the bottom). Sites for interaction with N-CoR and mSin3 are also shown as light blue and dark blue lines, respectively. All mutations (asterisks for missense variants and lines for deletions) are located in the R-SMAD binding domain. (B) Highly conserved amino acid residues (indicated in dark boxes) are conserved in vertebrates. All mutations affect highly conserved residues. The following abbreviations are used: Hs, Homo sapiens; Ms, Mus musculus; Cf, Canis familiaris; Bt, Bos Taurus; Mac, Macropus eugeneii; Gg, Gorilla gorilla; and Dr, Danio rerio.

Figure 3

Three-Dimensional Modeling of SKI (A) Functional domains of wild-type protein composed of an N-terminal DNA transcriptional regulating domain (dark blue) including R-SMAD (light blue) and DHD domains, a central SMAD4-interacting domain (greenish yellow), and a C-terminal coiled-coil domain (red). (B) Enlargement of the region affected by all the mutations. The in-frame deletions shorten a loop (between residues 92 and 97). The missense mutations disrupt a flexible region (residues 31–35). All the mutations are localized on the same surface of the R-SMAD-binding domain.