Molecular Diversity and Associated Phenotypic Spectrum of GermlineCBLMutations

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 candidate predisposition genes in individuals with cutaneous melanoma and at least two independent additional primary cancers

“…Pathogenic mutations described to date require a functional tyrosine kinase binding domain (TKB, from p.51 – 349) and disruption of the α-helix formed between the TKB and RING domains; the truncating mutation in our cohort (p.Glu658X) does not disrupt this interaction [ 34 ]. Additionally, the RASopathy associated mutations cluster around the RING domain, with described mutations occurring from p.Q367–R420 [ 35 ], which is before the protein disruption described in our patient. Therefore, while this variant is not part of the known autosomal dominant cancer syndrome spectrum, the functional impact of this variant in terms of general cancer susceptibility is unknown.…”

In vivo Functional Genomics for Undiagnosed Patients: The Impact of Small GTPases Signaling Dysregulation at Pan-Embryo Developmental Scale

“…Indeed, germline mutations affecting different components of signaling cascade are responsible for RASopathies, a group of developmental disorders comprising Noonan syndrome (NS), LEOPARD syndrome (NS with multiple lentigines), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), neurofibromatosis type 1 (NF-1), and other clinically related disorders, displaying high genetic and clinical FIGURE 1 | Schematic representation of Ras/MAPK cascade (left), Ras/MAPK-influenced pathways, and developmental processes (center) and examples of genetic conditions underlying a dysregulated cascade (right). For the diseases and disease-genes depicted here, besides the literature cited in the text, refer to Roberts et al (2007) and Tartaglia et al (2007) (SOS1 mutations in NS), Carta et al (2006); Pandit et al (2007); Cordeddu et al (2009); Cirstea et al (2010) (KRAS, NRAS, RAF1, and SHOC2 mutations in NS and related conditions), Aoki et al (2005Aoki et al ( , 2013 (HRAS mutations in CS), Flex et al (2014) (RRAS mutations in a RASopathy condition prone to cancer), Yamamoto et al (2015) (SOS2, LZTR1 mutations in NS), Martinelli et al (2010Martinelli et al ( , 2015; Pérez et al, 2010 (CBL mutations heterogeneity (for a comprehensive review of the work in the field, refer to Cox and Der, 2010;Tartaglia et al, 2011;Rauen, 2013;Simanshu et al, 2017;Tajan et al, 2018; and more recently Kang and Lee, 2019). It is also equally established that activating mutations in genes encoding members of the Ras/MAPK signaling are commonly associated with cancers (Malumbres and Barbacid, 2003).…”

“…FIGURE 1 | Schematic representation of Ras/MAPK cascade (left), Ras/MAPK-influenced pathways, and developmental processes (center) and examples of genetic conditions underlying a dysregulated cascade (right). For the diseases and disease-genes depicted here, besides the literature cited in the text, refer to Roberts et al (2007) and Tartaglia et al (2007) (SOS1 mutations in NS), Carta et al (2006); Pandit et al (2007); Cordeddu et al (2009); Cirstea et al (2010) (KRAS, NRAS, RAF1, and SHOC2 mutations in NS and related conditions), Aoki et al (2005, 2013) (HRAS mutations in CS), Flex et al (2014) (RRAS mutations in a RASopathy condition prone to cancer), Yamamoto et al (2015) (SOS2, LZTR1 mutations in NS),Martinelli et al (2010Martinelli et al ( , 2015;Pérez et al, 2010 (CBL mutations in a developmental syndrome prone to cancer), Urosevic et al (2011); Aoidi et al (2018) (BRAF, MEK1, or MEK2 mutations in CFCS), and Capri et al (2019) (RRAS2 mutations in NS).…”

Variability in clinical and neuropsychological features of individuals with MAP2K1 mutations

“…In addition, patients with mutations in KRAS frequently have a variable or “intermediate” phenotype that can resemble either CFC or NS, and these patients continue to be classified based on which diagnosis was the best fit with their clinical features [Nava et al, ; Stark et al, ]. Similarly, mutations in several other genes within the RAS/MAPK pathway (e.g., SHOC2, CBL ) cause “NS‐like” syndromes that are associated with characteristics of both NS and CFC, as well as with distinctive mutation‐specific features [Komatsuzaki et al, ; Martinelli et al, ]. Finally, even with an increasing number of identified genes, there are patients with a clinical diagnosis of CFC or NS in whom no molecular cause can be identified [Allanson et al, ; Aoki et al, ].…”