Identification of a novel de novo deletion in RAF1 associated with biventricular hypertrophy in Noonan syndrome.
Biventricular hypertrophy (BVH) is a disease state characterized by the thickening of the ventricle walls. The differential diagnosis of BVH with other congenital and familial diseases in which increased ventricle wall thickness is a prominent clinical feature is fundamental due to its therapeutic and prognostic value, mainly during infancy. We describe a 2-month-old infant presenting BVH. Using exome sequencing, we identified a novel de novo 3-bp deletion in the RAF1 gene that is located in the binding active site for the 14-3-3 peptide. Based on docking calculations, we demonstrate that this novel mutation impairs protein/target binding, thus constitutively activating Ras signaling, which is a dysregulation associated with Noonan syndrome. Finally, our study underlines the importance of molecular modeling to understand the roles of novel mutations in pathogenesis.
USSD Laboratorio di Genetica Medica, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
Maria Elena
ME
Sana
Andrea
A
Spitaleri
Dimitrios
D
Spiliotopoulos
Laura
L
Pezzoli
Laura
L
Preda
Giovanna
G
Musco
Paolo
P
Ferrazzi
Maria
M
Iascone
D048948:14-3-3 Proteins / Q000737:chemistry / Q000378:metabolism; D000328:Adult; D001665:Binding Sites; D006332:Cardiomegaly / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D017353:Gene Deletion; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D009634:Noonan Syndrome / Q000175:diagnosis / Q000235:genetics*; D011485:Protein Binding; D011487:Protein Conformation; D019908:Proto-Oncogene Proteins c-raf / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D048948:14-3-3 Proteins; D019908:Proto-Oncogene Proteins c-raf
14-3-3 protein; Noonan syndrome; RAF1; biventricular hypertrophy; computational modeling; exome sequencing