title: 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.
authors.affiliation: Equipe d'Accueil 4271, Equipe Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Carmignac
authors.forename: Julien
authors.initials: J
authors.lastname: Thevenon
authors.forename: Lesley
authors.initials: L
authors.lastname: Adès
authors.forename: Bert
authors.initials: B
authors.lastname: Callewaert
authors.forename: Sophie
authors.initials: S
authors.lastname: Julia
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.forename: Lucie
authors.initials: L
authors.lastname: Gueneau
authors.forename: Jean-Benoit
authors.initials: JB
authors.lastname: Courcet
authors.forename: Estelle
authors.initials: E
authors.lastname: Lopez
authors.forename: Katherine
authors.initials: K
authors.lastname: Holman
authors.forename: Marjolijn
authors.initials: M
authors.lastname: Renard
authors.forename: Henri
authors.initials: H
authors.lastname: Plauchu
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Plessis
authors.forename: Julie
authors.initials: J
authors.lastname: De Backer
authors.forename: Anne
authors.initials: A
authors.lastname: Child
authors.forename: Gavin
authors.initials: G
authors.lastname: Arno
authors.forename: Laurence
authors.initials: L
authors.lastname: Duplomb
authors.forename: Patrick
authors.initials: P
authors.lastname: Callier
authors.forename: Bernard
authors.initials: B
authors.lastname: Aral
authors.forename: Pierre
authors.initials: P
authors.lastname: Vabres
authors.forename: Nadège
authors.initials: N
authors.lastname: Gigot
authors.forename: Eloisa
authors.initials: E
authors.lastname: Arbustini
authors.forename: Maurizia
authors.initials: M
authors.lastname: Grasso
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.forename: Clarisse
authors.initials: C
authors.lastname: Baumann
authors.forename: Maja
authors.initials: M
authors.lastname: Di Rocco
authors.forename: Jaime
authors.initials: J
authors.lastname: Sanchez Del Pozo
authors.forename: Frédéric
authors.initials: F
authors.lastname: Huet
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jondeau
authors.forename: Gwenaëlle
authors.initials: G
authors.lastname: Collod-Beroud
authors.forename: Christophe
authors.initials: C
authors.lastname: Beroud
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Rivière
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Anne
authors.initials: A
authors.lastname: De Paepe
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D054119:Arachnodactyly / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003398:Craniosynostoses / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D005091:Exons; D019066:Facies; D005260:Female; D023061:Gene Order; D005799:Genes, Dominant; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C060614:SKI protein, human