Molecular Diversity and Associated Phenotypic Spectrum of Germline CBL Mutations

Simone Martinelli, Emilia Stellacci, Luca Pannone, Daniela D'Agostino, Federica Consoli, Christina Lissewski, Marianna Silvano, Giulia Cencelli, Francesca Lepri, Silvia Maitz, Silke Pauli, Anita Rauch, Giuseppe Zampino, Angelo Selicorni, Serge Melançon, Maria C. Digilio, Bruce D. Gelb, Alessandro De Luca, Bruno Dallapiccola, Martin ZenkerMarco Tartaglia

Research output: Contribution to journalArticle

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. Germline mutations in CBL cause a leukemia-prone disorder clinically related to Noonan syndrome. Here, we explored the spectrum of CBL mutationsand their associated phenotype. Five different mutations are identified, including a novel nonsense change generating a v-Cbl-like protein able to enhance signaling through RAS. Genotype-phenotype correlation analysis indicate that germline CBL mutations cause a variable phenotype characterized by a relatively high frequency of neurological features, predisposition to JMML, and low prevalence of cardiac defects and reduced growth.

Original languageEnglish
Pages (from-to)787-796
Number of pages10
JournalHuman Mutation
Volume36
Issue number8
DOIs
Publication statusPublished - Aug 1 2015

    Fingerprint

Keywords

  • CBL mutation-associated syndrome
  • Genotype-phenotype correlations
  • Noonan syndrome
  • RAS-MAPK

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Martinelli, S., Stellacci, E., Pannone, L., D'Agostino, D., Consoli, F., Lissewski, C., Silvano, M., Cencelli, G., Lepri, F., Maitz, S., Pauli, S., Rauch, A., Zampino, G., Selicorni, A., Melançon, S., Digilio, M. C., Gelb, B. D., De Luca, A., Dallapiccola, B., ... Tartaglia, M. (2015). Molecular Diversity and Associated Phenotypic Spectrum of Germline CBL Mutations. Human Mutation, 36(8), 787-796. https://doi.org/10.1002/humu.22809