In-Frame Mutations in Exon 1 of SKI Cause Dominant Shprintzen-Goldberg Syndrome

Virginie Carmignac 1 Julie Thevenon Lesley Ades 2 Bert Callewaert 3 Sophie Julia 4 Christel Thauvin-Robinet 5 Lucie Gueneau 6 Jean-Benoît Courcet 7 Estelle Lopez 8 Katherine Holman 9 Marjolijn Renard Henri Plauchu 10, 11 Ghislaine Plessis 12 Julie De Backer 13 Anne Child 14 Gavin Arno 14 Laurence Duplomb 15 Patrick Callier 16 Bernard Aral 17 Pierre Vabres 18 Nadège Gigot 6 Eloisa Arbustini 19 Maurizia Grasso 20 Peter N Robinson Cyril Goizet 21 Clarisse Baumann 22 Maja Di Rocco Jaime Sanchez del Pozo Frédéric Huet 23 Guillaume Jondeau 24 Gwenaëlle Collod-Béroud 25 Christophe Béroud 25 Jeanne Amiel Valérie Cormier-Daire 26 Jean-Baptiste Rivière 5 Catherine Boileau 24 Anne De Paepe 27 Laurence Faivre 16
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.
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American Journal of Human Genetics, Elsevier (Cell Press), 2012, 91 (5), pp.950 - 957. 〈10.1016/j.ajhg.2012.10.002〉
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Virginie Carmignac, Julie Thevenon, Lesley Ades, Bert Callewaert, Sophie Julia, et al.. In-Frame Mutations in Exon 1 of SKI Cause Dominant Shprintzen-Goldberg Syndrome. American Journal of Human Genetics, Elsevier (Cell Press), 2012, 91 (5), pp.950 - 957. 〈10.1016/j.ajhg.2012.10.002〉. 〈hal-01670135〉

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