Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype Simone Martinelli, Alessandro De Luca, Emilia.

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Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype Simone Martinelli, Alessandro De Luca, Emilia Stellacci, Cesare Rossi, Saula Checquolo, Francesca Lepri, Viviana Caputo, Marianna Silvano, Francesco Buscherini, Federica Consoli, Grazia Ferrara, Maria C. Digilio, Maria L. Cavaliere, Johanna M. van Hagen, Giuseppe Zampino, Ineke van der Burgt, Giovanni B. Ferrero, Laura Mazzanti, Isabella Screpanti, Helger G. Yntema, Willy M. Nillesen, Ravi Savarirayan, Martin Zenker, Bruno Dallapiccola, Bruce D. Gelb, Marco Tartaglia The American Journal of Human Genetics Volume 87, Issue 2, Pages 250-257 (August 2010) DOI: 10.1016/j.ajhg.2010.06.015 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 Germline CBL Mutations Underlying Noonan Syndrome and Related Phenotypes (A) Location of predicted amino acid substitutions associated with disease is shown below the CBL structure scheme. CBL comprises an N-terminal tyrosine kinase binding domain (TKB) connected by a linker to the RING-finger domain (RING) implicated in E2 enzyme binding. These domains are followed by a proline-rich region and a C-terminal portion containing sites of tyrosine phosphorylation (not shown) and a sequence homologous to both the ubiquitin-associated and leucine zipper domain (UBA/LZ). Numbers above the domain structure indicate the amino acid boundaries of those domains. (B) Electropherograms showing the identified heterozygous missense mutations. (C) Mutated amino acid residues in the three-dimensional structure of human CBL complexed with UBE2L3.40 Cα ribbon trace of the CBL tyrosine kinase binding domain (cyan), linker (orange), and RING-finger domain (red) of CBL are shown together with the interacting portion of UBE2L3 (gray). Mutated residues are indicated with their side chains as blue sticks. Residues of the linker and RING domain interact with the tyrosine kinase binding domain (orange and red respectively) or bind UBE2L3 (green and yellow, respectively); their side chains are also shown. Visualization and analysis of the molecular structure was performed with the program UCSF Chimera.54 (D) Facial features of the affected subjects carrying the c.1100A > C (Gln367Pro), c.1144A > G (Lys382Glu), c.1168G > T (Asp390Tyr) (at 5 years and 15 years), and c.1259G > A (Arg420Gln) (father and daughter) mutations. The American Journal of Human Genetics 2010 87, 250-257DOI: (10.1016/j.ajhg.2010.06.015) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 Functional Consequences of the Disease-Causing Asp390Tyr and Arg420Gln CBL Mutant Proteins (Left) EGFR ubiquitylation in COS-1 cells transiently expressing the Asp390Tyr, Arg420Gln, and wild-type CBL proteins after EGF stimulation (100 ng/ml, 1 hr). EGFR ubiquitylation (anti-ubiquitin, Santa Cruz Biotech, sc-8017) was determined on immunoprecipitated EGFR (Cell Signaling, #4267). Immunoprecipated EGFR, and expression levels of exogenous CBL (anti-HA antibody, Sigma, H3663) and EGFR proteins and β-actin (Sigma, A5441) in cell lysates are also shown. Blots are representative of three experiments performed. (Right) AKT and ERK phosphorylation assays in COS-1 cells transiently expressing the Asp390Tyr, Arg420Gln, and wild-type CBL proteins. Protein phosphorylation status (pAKT, Cell Signaling, #9271; pERK1/2, Cell Signaling, #9106) was evaluated in time-course experiments basally or after EFG stimulation. AKT (Cell Signaling, #9272), ERK1/2 (Cell Signaling, #9102) and CBL (anti-HA, see above) expression levels are also shown. The American Journal of Human Genetics 2010 87, 250-257DOI: (10.1016/j.ajhg.2010.06.015) Copyright © 2010 The American Society of Human Genetics Terms and Conditions