In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome.
Am J Hum Genet
; 91(5): 950-7, 2012 Nov 02.
Article
in En
| MEDLINE
| ID: mdl-23103230
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-ß 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-ß-signaling pathway.
Full text:
1
Database:
MEDLINE
Main subject:
Exons
/
Proto-Oncogene Proteins
/
Craniosynostoses
/
DNA-Binding Proteins
/
Arachnodactyly
/
Genes, Dominant
/
Marfan Syndrome
/
Mutation
Type of study:
Prognostic_studies
Limits:
Adolescent
/
Adult
/
Child
/
Child, preschool
/
Female
/
Humans
/
Male
Language:
En
Journal:
Am J Hum Genet
Year:
2012
Type:
Article
Affiliation country:
France