Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype
Open accessAbstract
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.
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CBL mutations give rise to a Noonan syndrome-like disorder.
“when mutated, has been shown to give rise to a Noonan syndrome-like disorder [75].”
From Self-domestication in Homo sapiens: Insights from comparative genomics (2017) · cites this paper as [75]
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- Authors
- Martinelli, S., De Luca, A., Stellacci, E., Rossi, C., Checquolo, S., Lepri, F., Caputo, V., Silvano, M., Buscherini, F., Consoli, F., Ferrara, G., Digilio, M. C., Cavaliere, M. L., van Hagen, J. M., Zampino, G., van der Burgt, I., Ferrero, G. B., Mazzanti, L., Screpanti, I., Yntema, H. G., Nillesen, W. M., Savarirayan, R., Zenker, M., Dallapiccola, B., Gelb, B. D., & Tartaglia, M.
- Affiliations
- Istituto Superiore di Sanità (IT)
- IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
- Sapienza University of Rome (IT)
- Casa Sollievo della Sofferenza (IT)
- Bambino Gesù Children's Hospital (IT)
- Ospedale Antonio Cardarelli (IT)
- Università Cattolica del Sacro Cuore (IT)
- University of Turin (IT)
- University of Bologna (IT)
- Radboud University Medical Center (NL)
- Royal Children's Hospital (AU)
- University Hospital Magdeburg (DE)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Tartaglia, Marco
- ORCID
- Martinelli, Simone
- Stellacci, Emilia
- Rossi, Cesare
- Checquolo, Saula
- Lepri, Francesca
- Caputo, Viviana
- Silvano, Marianna
- Consoli, Federica
- Ferrara, Grazia
- Digilio, Maria C.
- Cavaliere, Maria L.
- Zampino, Giuseppe
- Ferrero, Giovanni B.
- Mazzanti, Laura
- Screpanti, Isabella
- Yntema, Helger G.
- Savarirayan, Ravi
- Zenker, Martin
- Dallapiccola, Bruno
- Gelb, Bruce D.
- Tartaglia, Marco
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2010-08
- Volume
- 87
- Issue
- 2
- Pages
- 250-257
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2917705
- OpenAlex
- W2091931718
- Cited by
- 259
- References
- 54
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 17 · 2023: 9 · 2022: 25 · 2021: 19 · 2020: 15 · 2019: 8 · 2018: 11 · 2017: 24 · 2016: 19 · 2015: 15 · 2014: 22 · 2013: 19 · 2012: 19
- FWCI
- 8.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Ministero della Salute
- Consiglio Nazionale delle Ricerche
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL 71207, R01HL071207)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- CBL, Noonan syndrome, germline mutations, Ras signaling, E3 ubiquitin ligase, RING domain, tumor suppressor, developmental disorders, heart disease, facial dysmorphism, cancer susceptibility, phenotypic heterogeneity
- MeSH terms
- Base Sequence, DNA Mutational Analysis, Female, Heterozygote, Humans, Male, Molecular Sequence Data, Noonan Syndrome, Phenotype, Germ-Line Mutation, Amino Acid Substitution, Tumor Suppressor Proteins, Mutant Proteins, Proto-Oncogene Proteins c-cbl
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