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

Am J Hum Genet. 2012 Nov 2;91(5):950-7. doi: 10.1016/j.ajhg.2012.10.002. Epub 2012 Oct 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Arachnodactyly / genetics*
  • Child
  • Child, Preschool
  • Craniosynostoses / genetics*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • Exons*
  • Facies
  • Female
  • Gene Order
  • Genes, Dominant*
  • Humans
  • Male
  • Marfan Syndrome / genetics*
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Phenotype
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / genetics*
  • Sequence Alignment
  • Young Adult

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • SKI protein, human

Supplementary concepts

  • Shprintzen Golberg craniosynostosis