TY - JOUR
T1 - Molecular Diversity and Associated Phenotypic Spectrum of Germline CBL Mutations
AU - Martinelli, Simone
AU - Stellacci, Emilia
AU - Pannone, Luca
AU - D'Agostino, Daniela
AU - Consoli, Federica
AU - Lissewski, Christina
AU - Silvano, Marianna
AU - Cencelli, Giulia
AU - Lepri, Francesca
AU - Maitz, Silvia
AU - Pauli, Silke
AU - Rauch, Anita
AU - Zampino, Giuseppe
AU - Selicorni, Angelo
AU - Melançon, Serge
AU - Digilio, Maria C.
AU - Gelb, Bruce D.
AU - De Luca, Alessandro
AU - Dallapiccola, Bruno
AU - Zenker, Martin
AU - Tartaglia, Marco
PY - 2015/8/1
Y1 - 2015/8/1
N2 - 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.
AB - 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.
KW - CBL mutation-associated syndrome
KW - Genotype-phenotype correlations
KW - Noonan syndrome
KW - RAS-MAPK
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U2 - 10.1002/humu.22809
DO - 10.1002/humu.22809
M3 - Article
C2 - 25952305
AN - SCOPUS:84937733742
VL - 36
SP - 787
EP - 796
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 8
ER -