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

V Carmignac, J Thevenon, L Adès, B Callewaert… - The American Journal of …, 2012 - cell.com
V Carmignac, J Thevenon, L Adès, B Callewaert, S Julia, C Thauvin-Robinet, L Gueneau…
The American Journal of Human Genetics, 2012cell.com
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 …
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.
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