title: Molecular Diversity and Associated Phenotypic Spectrum of Germline CBL Mutations.
abstract: Noonan syndrome (NS) is a relatively common developmental disorder with a pleomorphic phenotype. Mutations causing NS alter genes encoding proteins involved in the RAS-MAPK pathway. We and others identified Casitas B-lineage lymphoma proto-oncogene (CBL), which encodes an E3-ubiquitin ligase acting as a tumor suppressor in myeloid malignancies, as a disease gene underlying a condition clinically related to NS. Here, we further explored the spectrum of germline CBL mutations and their associated phenotype. CBL mutation scanning performed on 349 affected subjects with features overlapping NS and no mutation in NS genes allowed the identification of five different variants with pathological significance. Among them, two splice-site changes, one in-frame deletion, and one missense mutation affected the RING domain and/or the adjacent linker region, overlapping cancer-associated defects. A novel nonsense mutation generating a v-Cbl-like protein able to enhance signal flow through RAS was also identified. Genotype-phenotype correlation analysis performed on available records indicated that germline CBL mutations cause a variable phenotype characterized by a relatively high frequency of neurological features, predisposition to juvenile myelomonocytic leukemia, and low prevalence of cardiac defects, reduced growth, and cryptorchidism. Finally, we excluded a major contribution of two additional members of the CBL family, CBLB and CBLC, to NS and related disorders.
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.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Stellacci
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.|Dipartimento di Medicina Sperimentale, Sapienza Università di Roma, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Pannone
authors.affiliation: Department of Medical Genetics, McGill University Health Centre, Montreal Children's Hospital, Montreal, Quebec, Canada.
authors.forename: Daniela
authors.initials: D
authors.lastname: D'Agostino
authors.affiliation: Dipartimento di Medicina Sperimentale, Sapienza Università di Roma, Rome, Italy.|Laboratorio Mendel, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza, Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Consoli
authors.affiliation: Institute of Human Genetics, University Hospital of Magdeburg, Otto-von-Guericke-University, Magdeburg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Lissewski
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Silvano
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Cencelli
authors.affiliation: Ospedale Pediatrico "Bambino Gesù", Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lepri
authors.affiliation: Dipartimento di Pediatria, Genetica Clinica, Ospedale S. Gerardo, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Maitz
authors.affiliation: Institute of Human Genetics, University of Göttingen, Göttingen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Pauli
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland.
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.affiliation: Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.affiliation: Dipartimento di Pediatria, Genetica Clinica, Ospedale S. Gerardo, Università di Milano-Bicocca, Monza, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Selicorni
authors.affiliation: Department of Medical Genetics, McGill University Health Centre, Montreal Children's Hospital, Montreal, Quebec, Canada.
authors.forename: Serge
authors.initials: S
authors.lastname: Melançon
authors.affiliation: Ospedale Pediatrico "Bambino Gesù", Rome, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Digilio
authors.affiliation: Mindich Child Health and Development Institute and Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.affiliation: Laboratorio Mendel, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: De Luca
authors.affiliation: Ospedale Pediatrico "Bambino Gesù", Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.affiliation: Institute of Human Genetics, University Hospital of Magdeburg, Otto-von-Guericke-University, Magdeburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
mesh_terms: D002675:Child, Preschool; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D009634:Noonan Syndrome / Q000235:genetics / Q000503:physiopathology; D000090063:Proto-Oncogene Mas; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics* / Q000378:metabolism
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human
keywords: CBL mutation-associated syndrome; Noonan syndrome; RAS-MAPK; genotype-phenotype correlations