title: Noonan syndrome associated with both a new Jnk-activating familial SOS1 and a de novo RAF1 mutations.
abstract: Noonan syndrome is a genetic condition characterized by congenital heart defects, short stature, and characteristic facial features. Familial or de novo mutations in PTPN11, RAF1, SOS1, KRAS, and NRAS are responsible for 60-75% of the cases, thus, additional genes are expected to be involved in the pathogenesis. In addition, the genotype-phenotype correlation has been hindered by the highly variable expressivity of the disease. For all these reasons, expanding the genotyped and clinically evaluated case numbers will benefit the clinical community. A mutation analysis has been performed on RAF1, SOS1, and GRB2, in 24 patients previously found to be negative for PTPN11 and KRAS mutations. We identified four mutations in SOS1 and one in RAF1, while no GRB2 variants have been found. Interestingly, the RAF1 mutation was present in a patient also carrying a newly identified p.R497Q familial SOS1 mutation, segregating with a typical Noonan Syndrome SOS1 cutaneous phenotype. Functional analysis demonstrated that the R497Q SOS1 mutation leads to Jnk activation, but has no effect on the Ras effector Erk1. We propose that this variant might contribute to the onset of the peculiar ectodermal traits displayed by the propositus amidst the more classical Noonan syndrome presentation. To our knowledge, this is the first reported case of a patient harboring mutations in two genes, with an involvement of both Ras and Rac1 pathways, indicating that SOS1 may have a role of modifier gene that might contribute the variable expressivity of the disease, evidencing a genotype-phenotype correlation in the family.
authors.affiliation: Dipartimento di Biologia e Genetica per le Scienze Mediche, Università degli Studi di Milano, Milano, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Longoni
authors.forename: Silvia
authors.initials: S
authors.lastname: Moncini
authors.forename: Mariangela
authors.initials: M
authors.lastname: Cisternino
authors.forename: Ilaria M
authors.initials: IM
authors.lastname: Morella
authors.forename: Serena
authors.initials: S
authors.lastname: Ferraiuolo
authors.forename: Silvia
authors.initials: S
authors.lastname: Russo
authors.forename: Savina
authors.initials: S
authors.lastname: Mannarino
authors.forename: Valeria
authors.initials: V
authors.lastname: Brazzelli
authors.forename: Paola
authors.initials: P
authors.lastname: Coi
authors.forename: Renata
authors.initials: R
authors.lastname: Zippel
authors.forename: Marco
authors.initials: M
authors.lastname: Venturin
authors.forename: Paola
authors.initials: P
authors.lastname: Riva
mesh_terms: D004252:DNA Mutational Analysis; D005190:Family; D051380:GRB2 Adaptor Protein / Q000235:genetics*; D005838:Genotype; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020125:Mutation, Missense; D009634:Noonan Syndrome / Q000235:genetics*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D020837:SOS1 Protein / Q000235:genetics*; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins
chemical_list: D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D020837:SOS1 Protein; D019908:Proto-Oncogene Proteins c-raf; D048031:JNK Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein; D018631:ras Proteins