title: Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype.
abstract: RAS signaling plays a key role in controlling appropriate cell responses to extracellular stimuli and participates in early and late developmental processes. Although enhanced flow through this pathway has been established as a major contributor to oncogenesis, recent discoveries have revealed that aberrant RAS activation causes a group of clinically related developmental disorders characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, ectodermal and musculoskeletal anomalies, and increased risk for certain malignancies. Here, we report that heterozygous germline mutations in CBL, a tumor-suppressor gene that is mutated in myeloid malignancies and encodes a multivalent adaptor protein with E3 ubiquitin ligase activity, can underlie a phenotype with clinical features fitting or partially overlapping Noonan syndrome (NS), the most common condition of this disease family. Independent CBL mutations were identified in two sporadic cases and two families from among 365 unrelated subjects who had NS or suggestive features and were negative for mutations in previously identified disease genes. Phenotypic heterogeneity and variable expressivity were documented. Mutations were missense changes altering evolutionarily conserved residues located in the RING finger domain or the linker connecting this domain to the N-terminal tyrosine kinase binding domain, a known mutational hot spot in myeloid malignancies. Mutations were shown to affect CBL-mediated receptor ubiquitylation and dysregulate signal flow through RAS. These findings document that germline mutations in CBL alter development to cause a clinically variable condition that resembles NS and that possibly predisposes to malignancies.
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Martinelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: De Luca
authors.forename: Emilia
authors.initials: E
authors.lastname: Stellacci
authors.forename: Cesare
authors.initials: C
authors.lastname: Rossi
authors.forename: Saula
authors.initials: S
authors.lastname: Checquolo
authors.forename: Francesca
authors.initials: F
authors.lastname: Lepri
authors.forename: Viviana
authors.initials: V
authors.lastname: Caputo
authors.forename: Marianna
authors.initials: M
authors.lastname: Silvano
authors.forename: Francesco
authors.initials: F
authors.lastname: Buscherini
authors.forename: Federica
authors.initials: F
authors.lastname: Consoli
authors.forename: Grazia
authors.initials: G
authors.lastname: Ferrara
authors.forename: Maria C
authors.initials: MC
authors.lastname: Digilio
authors.forename: Maria L
authors.initials: ML
authors.lastname: Cavaliere
authors.forename: Johanna M
authors.initials: JM
authors.lastname: van Hagen
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.forename: Ineke
authors.initials: I
authors.lastname: van der Burgt
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Ferrero
authors.forename: Laura
authors.initials: L
authors.lastname: Mazzanti
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.forename: Helger G
authors.initials: HG
authors.lastname: Yntema
authors.forename: Willy M
authors.initials: WM
authors.lastname: Nillesen
authors.forename: Ravi
authors.initials: R
authors.lastname: Savarirayan
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics; D009634:Noonan Syndrome / Q000235:genetics*; D010641:Phenotype; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D050505:Mutant Proteins; D025521:Tumor Suppressor Proteins; D050721:Proto-Oncogene Proteins c-cbl