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: 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 Zenker, Marco Tartaglia
• Journal: Human mutation (Hum Mutat) Vol. 36 Issue 8 Pg. 787-96 (Aug 2015) ISSN: 1098-1004 [Electronic] United States
• PMID: 25952305 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 WILEY PERIODICALS, INC.

Chemical References

• MAS1 protein, human
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-cbl
• CBL protein, human

Topics

• Child, Preschool
• Female
• Genetic Association Studies
• Genetic Variation
• Germ-Line Mutation
• Humans
• Male
• Noonan Syndrome (genetics, physiopathology)
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-cbl (genetics, metabolism)