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

Virginie Carmignac, Julien Thevenon, Lesley Adès, Bert Callewaert, Sophie Julia, Christel Thauvin-Robinet, Lucie Gueneau, Jean-Benoit Courcet, Estelle Lopez, Katherine Holman, Marjolijn Renard, Henri Plauchu, Ghislaine Plessis, Julie De Backer, Anne Child, Gavin Arno, Laurence Duplomb, Patrick Callier, Bernard Aral, Pierre Vabres, Nadège Gigot, Eloisa Arbustini, Maurizia Grasso, Peter N. Robinson, Cyril Goizet, Clarisse Baumann, Maja Di Rocco, Jaime Sanchez Del Pozo, Frédéric Huet, Guillaume Jondeau, Gwenaëlle Collod-Beroud, Christophe Beroud, Jeanne Amiel, Valérie Cormier-Daire, Jean-Baptiste Rivière, Catherine Boileau, Anne De Paepe, Laurence Faivre
The American Journal of Human Genetics. 2012-11-01; 91(5): 950-957
DOI: 10.1016/J.AJHG.2012.10.002


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

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

Carmignac V(1), Thevenon J, Adès L, Callewaert B, Julia S, Thauvin-Robinet C,
Gueneau L, Courcet JB, Lopez E, Holman K, Renard M, Plauchu H, Plessis G, De
Backer J, Child A, Arno G, Duplomb L, Callier P, Aral B, Vabres P, Gigot N,
Arbustini E, Grasso M, Robinson PN, Goizet C, Baumann C, Di Rocco M, Sanchez Del
Pozo J, Huet F, Jondeau G, Collod-Beroud G, Beroud C, Amiel J, Cormier-Daire V,
Rivière JB, Boileau C, De Paepe A, Faivre L.

Author information:
(1)Equipe d’Accueil 4271, Equipe Génétique des Anomalies du Développement,
Université de Bourgogne, Dijon, France.

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.

Copyright © 2012 The American Society of Human Genetics. Published by Elsevier
Inc. All rights reserved.

DOI: 10.1016/j.ajhg.2012.10.002
PMCID: PMC3487125
PMID: 23103230 [Indexed for MEDLINE]

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