Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: CBL
SNOMEDCT: 128832006, 277587001, 445227008, 783143001; ICD10CM: C93.3, C93.30;
Cytogenetic location: 11q23.3 Genomic coordinates (GRCh38): 11:119,206,339-119,308,149 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q23.3 | ?Juvenile myelomonocytic leukemia | 607785 | Autosomal dominant; Somatic mutation | 3 |
| Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia | 613563 | Autosomal dominant | 3 |
The CBL protein primarily functions as an E3 ubiquitin ligase and acts as a negative regulator of several receptor protein tyrosine kinase signaling pathways by targeting receptors for degradation and as an adaptor protein in tyrosine phosphorylation-dependent signaling (Thien et al., 2001; Fu et al., 2003).
Cas NS-1 is an acutely transforming murine retrovirus that induces pre-B and pro-B cell lymphomas. Molecular cloning showed that it was generated from the ecotropic Cas-Br-M virus by sequential recombinations with endogenous retroviral sequences and a cellular oncogene. Langdon et al. (1989) found that the oncogene sequence shows no homology with known oncogenes, but some similarity to the yeast transcriptional activator GCN4. A 100-kD gag-cbl fusion protein, with no detectable kinase activity, is responsible for the cellular transformation. The cellular homolog of v-cbl, present in mouse and human DNA, is expressed in a range of hemopoietic lineages.
Vulval induction during development of Caenorhabditis elegans is mediated by LET-23, a homolog of the mammalian epidermal growth factor receptor tyrosine kinase (131550). The sli-1 gene is a negative regulator of LET-23 and was shown by Yoon et al. (1995) to encode a protein similar to the mammalian protooncoprotein CBL2. The sli-1 and CBL2 proteins share approximately 55% amino acid identity over a stretch of 390 residues, which includes a C(3)HC(4) zinc-binding motif known as the RING finger, and multiple consensus binding sites for SRC homology 3 (SH3) domains. The authors stated that sli-1 and CBL2 may define a new class of proteins that modify receptor tyrosine kinase-mediated signal transduction.
Nau and Lipkowitz (2003) determined that the open reading frame of the CBL gene contains 16 exons and spans more than 110 kb.
Wei et al. (1990) mapped the CBL gene to chromosome 11q23.3-qter by molecular characterization of the breakpoints in 2 somatic cell hybrids.
Jones et al. (1994) localized the rare folate-sensitive fragile site FRA11B (previously mapped to 11q23.3) to an interval of approximately 100 kb containing the 5-prime end of the CBL2 gene, which included a CCG trinucleotide repeat. Since all 4 folate-sensitive fragile sites that had been cloned at that time (i.e., FRAXA, FRAXE, FRAXF, and FRA16A) were known to consist of expanded CCG repeats, Jones et al. (1995) considered the CBL2 repeat as a likely candidate for the location of FRA11B. Furthermore, they presented evidence that expansion of the CCG(n) repeat is involved in the pathogenesis of Jacobsen syndrome (147791), which is the clinical presentation of the loss of part of the long arm of chromosome 11, typically from band 11q23 to 11qter.
Ubiquitination of receptor protein-tyrosine kinases (PTKs) terminates signaling by marking active receptors for degradation. CBL is an adaptor protein for receptor PTKs. It positively regulates receptor PTK ubiquitination in a manner dependent on its variant SH2 and RING finger domains. Ubiquitin-protein ligases, also known as E3s, are the components of ubiquitination pathways that recognize target substrates and promote their ligation to ubiquitin. Joazeiro et al. (1999) determined that the CBL protein acts as an E3 that can recognize tyrosine-phosphorylated substrates, such as the activated platelet-derived growth factor receptor (see 173410), through its SH2 domain. It recruits and allosterically activates an E2 ubiquitin-conjugating enzyme through its RING domain. Joazeiro et al. (1999) concluded that these results reveal an SH2-containing protein that functions as a ubiquitin-protein ligase and thus provide a distinct mechanism for substrate targeting in the ubiquitin system.
Thien et al. (2001) found that although mutations spanning the RING finger abolish CBL-directed polyubiquitination and downregulation of receptor PTKs (RPTKs), they do not induce transformation. In contrast, mutations within a highly conserved alpha-helical structure linking the SH2 and RING finger domains render CBL proteins oncogenic. Thus, CBL transformation involves effects additional to polyubiquitination of RPTKs that are independent of the RING finger and its ability to recruit E2-conjugating enzymes.
Insulin (176730) stimulates the transport of glucose into fat and muscle cells and initiates its actions by binding to its tyrosine kinase receptor (147670), leading to the phosphorylation of intracellular substrates. One such substrate is the CBL protooncogene product. CBL is recruited to the insulin receptor by interaction with the adaptor protein CAP (605264), through 1 of 3 adjacent SH3 domains in the C terminus of CAP. Upon phosphorylation of CBL, the CAP-CBL complex dissociates from the insulin receptor and moves to a caveolin (see 601047)-enriched triton-insoluble membrane fraction (Mastick et al., 1995). To identify a molecular mechanism underlying this subcellular redistribution, Baumann et al. (2000) screened a yeast 2-hybrid library using the N-terminal region of CAP and identified the caveolar protein flotillin (131560). Flotillin forms a ternary complex with CAP and CBL, directing the localization of the CAP-CBL complex to a lipid raft subdomain of the plasma membrane. Expression of the N-terminal domain of CAP in 3T3-L1 adipocytes blocks the stimulation of glucose transport by insulin, without affecting signaling events that depend on phosphatidylinositol-3-OH kinase (see 602838). Thus, localization of the CBL-CAP complex to lipid rafts generates a pathway that is crucial in the regulation of glucose uptake.
Using a yeast 2-hybrid screen of cDNA libraries with either the C-terminal proline-rich sequences or the distal part of CBL as bait, Soubeyran et al. (2002) showed interaction of CIN85 (300374) with the distal but not the pro-rich sequences of CBL. Immunoprecipitation analysis also indicated that the CBL-CIN85 interaction is enhanced in EGF (131530)-stimulated cells as a result of CBL phosphorylation and binding to EGF receptors. EGF stimulation results in a complex of CBL, CIN85, endophilins, and EGF receptors.
Petrelli et al. (2002) used a yeast 2-hybrid screen of a brain cDNA library with endophilin A3 (SH3GL3; 603362) as bait and identified CIN85, in addition to dynamins, as an interactor with SH3GL3. GST pull-down and immunoprecipitation analysis showed that the SH3 domains of the known endophilins are necessary and sufficient for binding. Stimulation of cells with HGF (142409) caused CBL to bind to HGFR (164860) through tyr1356 and induces HGFR ubiquitination. In addition, HGFR activation and phosphorylation led to CBL tyrosine phosphorylation and the recruitment of the CIN85-endophilin complex. Petrelli et al. (2002) proposed that this complex drives plasma membrane invagination and vesicle formation, resulting in negative modulation of signal transduction and biologic responses. They also suggested that the formation of this complex may represent a general way to downregulate activated tyrosine kinase receptors.
Shen et al. (2000) found that the Listeria monocytogenes surface protein InIB promoted bacterial entry into mammalian cells by binding to the extracellular domain of MET (164860). Veiga and Cossart (2005) found that L. monocytogenes InIB induced CBL-dependent monoubiquitination and endocytosis of MET and exploited the endocytosis to invade mammalian cells. In addition to MET, L. monocytogenes colocalized with EEA1 (605070), CBL, clathrin (see CLTC; 118955), and dynamin (see DNM1; 602377) during entry. Downregulation of CBL or RNA interference-mediated knockdown of major constituents of the endocytic machinery inhibited bacterial entry, indicating that the endocytic machinery is key to bacterial internalization.
Dragone et al. (2006) found that B-cell development was altered in mice deficient in both Slap (SLA; 601099) and Cbl. Overexpression of Slap and Cbl in a mature mouse B-cell line caused Slap to associate via its SH2 domain with proximal components of the B-cell receptor (BCR) complex. Slap and Cbl coexpression downregulated surface and total BCR levels, suggesting that SLAP and CBL function in intersecting pathways. Dragone et al. (2006) proposed that SLAP may be necessary to develop an optimal lymphocyte repertoire.
Using coimmunoprecipitation and ubiquitylation experiments, Rathinam and Flavell (2010) demonstrated an interaction between c-CBL and the IL7 receptor-alpha (IL7R; 146661) subunit and showed that c-CBL is involved in the ubiquitylation of IL7R.
Disruption in Cancer
Savage et al. (1991) studied the relation of CBL2 to the breakpoints in malignancies with translocations involving chromosome 11. CBL2 was translocated from chromosome 11 to 4 in an acute leukemia cell line possessing a t(4;11)(q21;q23) and from chromosome 11 to 14 in a B-cell lymphoma with a t(11;14)(q23;q32). CBL2 remained on chromosome 11 in a Ewing sarcoma cell line (612219) with a t(11;22)(q23;q12). Other studies indicated that NCAM (116930) and the genes for the 3 subunits of CD3 were all proximal to the tightly clustered THY1 (188230), ETS1 (164720), and CBL2 in 11q23.
CBL/MLL Fusion Gene
CBL lies on 11q23.3 telomeric to MLL (159555), which is frequently fused to loci on other chromosomes by the mechanism of translocations, causing various types of leukemia. Fu et al. (2003) found that CBL was fused to MLL in an adult patient with de novo acute myeloid leukemia (FAB M1) (AML; 601626). MLL exon 6 was fused in-frame with CBL exon 8. The genomic junction region involved the fusion of the 3-prime portion of an Alu element in intron 6 of MLL with the 5-prime portion of an Alu element in intron 7 of CBL. The absence of extensive sequence similarity at both breakpoints of MLL and CBL indicated that the recombination was not generated through homologous recombination. The transcriptional orientation of both genes is from centromere to telomere. The results of Southern blot analysis in conjunction with FISH suggested that the CBL/MLL fusion was the result of an interstitial deletion. CBL was the second gene at 11q23.3 found to fuse with MLL, the first being LARG (604763), a guanine nucleotide exchange factor which maps telomeric to CBL.
Germline Mutations in Noonan Syndrome-like Disorder and/or Juvenile Myelomonocytic Leukemia
Martinelli et al. (2010) identified 4 different heterozygous mutations in the CBL gene (165360.0001-165360.0004) in 4 unrelated probands with Noonan syndrome-like disorder (NSLL; 613563). Two of the mutations were de novo, and 2 were inherited from an affected father. Clinical features were highly variable, but included dysmorphic facial features, developmental delay, hyperextensible joints, thorax abnormalities, and cardiac defects. None of the patients developed a hematologic malignancy. In vitro functional expression studies showed that the mutations all caused impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion. These results were compatible with dysregulated intracellular signaling through RAS (see 190020).
In 3 unrelated patients with a Noonan syndrome-like disorder with juvenile myelomonocytic leukemia, Perez et al. (2010) identified a heterozygous germline mutation in the CBL gene (Y371H; 165360.0005). The mutation occurred de novo in 2 patients and was inherited from an unaffected father in 1 patient. Leukemia cells of all patients showed somatic loss of heterozygosity at chromosome 11q23, including the CBL gene. The findings indicated that heterozygous mutation in the CBL gene is associated with predisposition for the development of JMML.
From 27 leukemic patient samples, Loh et al. (2009) examined in detail leukemic cells from 3 patients and found acquired isodisomy of chromosome 11q including the CBL gene. Each of these 3 patients had a heterozygous germline CBL mutation, whereas their tumor cells had homozygous mutations. The finding that heterozygous germline mutations may predispose to development of JMML suggested that CBL acts as a tumor suppressor gene. Niemeyer et al. (2010) reported 21 children with JMML who had homozygous CBL mutations in leukemic cells. Sixteen of 21 patients had been previously reported by Loh et al. (2009). Normal tissue from 17 of 21 children was found to harbor a heterozygous germline mutation (see, e.g., 165360.0005-165360.0009), and normal tissue from 4 children was not available for analysis. A large percentage of these children showed dysmorphic features, developmental delay, cryptorchidism, and impaired growth, consistent with a Noonan syndrome-like disorder. The leukemia improved spontaneously in 5 of 6 children who did not undergo transplantation, even though the homozygous CBL mutation persisted in peripheral blood. In addition, 4 of these patients developed clinical signs consistent with vascular pathology, including optic atrophy, hypertension and an acquired cardiomyopathy; 1 had Takayasu arteritis. Niemeyer et al. (2010) postulated that the CBL mutation contributed to dysregulated lymphocyte signaling and vasculitis.
In 3 affected members of a family with juvenile myelomonocytic leukemia (JMML; 607785) without features of Noonan syndrome, Pathak et al. (2015) identified a germline heterozygous missense mutation in the CBL gene (Y371C; 165360.0009). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was also present in 4 family members without JMML, consistent with incomplete penetrance. Structural modeling predicted that the mutation would abrogate the ability of the mutant protein to adopt a conformation that would permit protein ubiquitination. Functional studies were not performed.
Somatic Mutations
Sanada et al. (2009) showed unique somatic gain-of-function mutations of the CBL tumor suppressor that are tightly associated with an acquired uniparental disomy (UPD) of the 11q arm in myeloid neoplasms showing myeloproliferative features. The CBL protooncogene encodes a 3-prime ubiquitin ligase and negatively regulates signal transduction of tyrosine kinase. Homozygous CBL mutations were found in most 11q acquired UPD-positive myeloid malignancies. Although the Cbl mutations were oncogenic in NIH3T3 cells, Cbl was shown to functionally and genetically act as a tumor suppressor. CBL mutants did not have E3 ubiquitin ligase activity, but inhibited that of wildtype CBL and CBLB (604491), leading to prolonged activation of tyrosine kinases after cytokine stimulation. Cbl-null hematopoietic stem/progenitor cells (HSPCs) showed enhanced sensitivity to a variety of cytokines compared to Cbl homozygous wildtype HSPCs, and transduction of CBL mutants into Cbl-null HSPCs further augmented their sensitivities to a broader spectrum of cytokines, including stem-cell factor (SCF; 184745), thrombopoietin (THPO; 600044), IL3 (147740), and FLT3 ligand (FLT3LG; 600007), indicating the presence of a gain of function that could not be attributed to a simple loss of function. The gain-of-function effects of CBL mutants on cytokine sensitivity of HSPCs largely disappeared in a CBL wildtype background or by cotransduction of wildtype CBL, which suggested the pathogenic importance of loss of wildtype CBL alleles found in most cases of CBL-mutated myeloid neoplasms. Sanada et al. (2009) concluded that their findings provided insight into a role of gain-of-function mutations of a tumor suppressor associated with acquired UPD in the pathogenesis of some myeloid cancer subsets, including AML (601626) and CML and refractory anemia with excess blasts.
In 27 of 159 leukemia samples from patients with juvenile myelomonocytic leukemia (JMML; 607785), Loh et al. (2009) identified 25 homozygous and 2 heterozygous mutations in the CBL gene. The mutations were located throughout the linker and RING finger domains, with the most common affected residue being tyr371 (see, e.g., 165370.0004). Leukemic cells exhibited CFU-GM hypersensitivity and high levels of STAT5 (601511) in response to GM-CSF. These findings indicated that reduplication of an inherited CBL mutation in a pluripotent hematopoietic stem cell confers a selective advantage for the homozygous state. Loh et al. (2009) estimated the frequency of CBL mutations to be 10 to 15% of JMML patients overall. They did not find CBL mutations in JMML patients with known mutations in PTPN11 (176876)/RAS (KRAS, 190070; NRAS, 164790) genes, indicating that CBL and PTPN11/RAS mutations are mutually exclusive. Loh et al. (2009) also found isolated CBL mutations in 4 of 44 samples from patients with chronic myelomonocytic leukemia (CMML; see 607785), which shares features with JMML.
Muramatsu et al. (2010) identified uniparental disomy of 11q23 in leukemic cells from 4 of 49 patients with JMML. Mutational analysis of the CBL gene identified somatic mutations in 5 (10%) of the 49 patients. Four patients were homozygous, 1 was heterozygous, and all CBL mutations occurred in the ring finger domain. None of these patients had mutations in other genes involved in the RAS signaling pathway, and none had mutations in members of the CBL family, the CBLB (604491) or CBLC (608453) genes.
Associations Pending Confirmation
See 165360.0010 for a discussion of a possible association between variation in the CBL gene and developmental and epileptic encephalopathy (see 308350).
Naramura et al. (2002) generated double-knockout (dKO) mice lacking both Cbl and Cblb (604491). They found that dKO T cells were hyperresponsive to anti-CD3 (see 186740) stimulation, although the major T-cell receptor (TCR; see 186880) signaling pathways were not enhanced. The dKO T cells failed to modulate surface TCR after ligand engagement, resulting in sustained TCR signaling. Naramura et al. (2002) proposed that the CBL family proteins negatively regulate T-cell activation by promoting clearance of engaged TCR from the cell surface, which appears to be necessary for the termination of TCR signals.
In Cbl -/- mice, Molero et al. (2004) observed a profound increase in whole-body energy expenditure as determined by increased core temperature and whole-body oxygen consumption. The null mice displayed a decrease in adiposity, primarily due to a reduction in cell size despite an increase in food intake, as well as a significant increase in activity. In addition, Cbl -/- mice displayed a marked improvement in whole-body insulin action, primarily due to changes in muscle metabolism. The authors observed increased protein levels of the insulin receptor and uncoupling protein-3 (602044) in skeletal muscle and a significant increase in the phosphorylation of AMP-activated protein kinase (see PRKAA1; 602739) and acetyl-CoA carboxylase (see ACACA; 200350). Molero et al. (2004) suggested that CBL plays an integral role in whole-body fuel homeostasis by regulating whole-body energy expenditure and insulin action.
Rathinam and Flavell (2010) found that c-Cbl-deficient mice developed an age-dependent lymphopenia. Mutant mice had normal frequencies of lymphocytes at age 4 weeks, but both B- and T-lymphocyte development and function were remarkably diminished at age 24 weeks compared to controls. Transplantation and in vitro studies showed that lymphocytes derived from mutant mice had an intrinsic cell defect related to hyperresponsiveness to IL7 (146660) due to increased expression of IL7R-alpha (146661) on the cell surface. Both B and T cells require specific expression levels of IL7R-alpha during development for proper differentiation. Overall, the findings indicated that a defect in c-Cbl results in dysregulation of IL7R-alpha expression, which causes reduced differentiation of B and T cells.
In a boy with Noonan syndrome-like disorder (NSLL; 613563), Martinelli et al. (2010) identified a heterozygous de novo 1100A-C transversion in the CBL gene, resulting in a gln367-to-pro (Q367P) substitution in a region adjacent to the linker connecting the RING finger domain to the N-terminal TKB domain. The Q367P mutation was not detected in 400 population-matched controls. Clinical features included dysmorphic facial features, developmental delay, congenital heart defect, and cafe-au-lait spots. In vitro functional expression studies showed that the mutation caused impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion. These results were compatible with dysregulated intracellular signaling through RAS.
In an 18-year-old girl who fulfilled the diagnostic criteria for Noonan syndrome (NSLL; 613563), Martinelli et al. (2010) identified a heterozygous 1144A-G transition in the CBL gene, resulting in a lys382-to-glu (K382E) substitution in the RING finger domain. The K382E mutation was not detected in 400 population-matched controls. Clinical features included short stature, distinctive facial features, short neck, hyperextensible joints, and conductive hearing loss, among others. The mutation was inherited from the father, who was originally thought to be unaffected, but on reevaluation was found to have mild signs, including broad neck, low posterior hairline, and Chiari type 1 malformation complicated by hydrocephalus and cervical syringomyelia. In vitro functional expression studies showed that the mutation caused impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion. These results were compatible with dysregulated intracellular signaling through RAS.
In a girl with Noonan syndrome-like disorder (NSLL; 613563), Martinelli et al. (2010) identified a heterozygous de novo 1168G-T transversion in the CBL gene, resulting in an asp390-to-tyr (D390Y) substitution in the RING finger domain. The D390Y mutation was not detected in 400 population-matched controls. Clinical features included developmental delay, dysmorphic facial features, hypotonia, and joint laxity. In vitro functional expression studies showed that the mutation caused impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion, as well as constitutive ERK phosphorylation. These results were compatible with dysregulated intracellular signaling through RAS.
In a father and daughter with Noonan syndrome-like disorder (NSLL; 613563), Martinelli et al. (2010) identified a heterozygous 1259G-A transition in the CBL gene, resulting in an arg420-to-gln (R420Q) substitution in the RING finger domain. The R420Q mutation was not detected in 400 population-matched controls. In vitro functional expression studies showed that the mutation caused impaired CBL-mediated degradation of cell-surface receptors in a dominant-negative fashion. These results were compatible with dysregulated intracellular signaling through RAS.
In 3 unrelated patients with Noonan syndrome-like disorder and onset of juvenile myelomonocytic leukemia (JMML) in the first years of life (NSLL; 613563), Perez et al. (2010) identified a heterozygous germline 1111T-C transition in exon 8 of the CBL gene, resulting in a tyr371-to-his (Y371H) substitution. Phosphorylation of tyr371 is essential for the E3 activity of CBL and for its interaction with a number of signaling proteins. Leukemic cells from all patients showed loss of heterozygosity at chromosome 11q23, including the CBL gene. The patients all demonstrated subtle developmental defects, including dysmorphic facial features and poor growth, and 1 patient had developmental delay.
Loh et al. (2009) identified a heterozygous germline Y371H mutation in 3 unrelated children with JMML, whereas leukemic cells from all 3 patients showed homozygosity for the mutation. Additional phenotypic features were not reported. Leukemic samples from 7 additional patients contained homozygous Y371H mutations. Germline/somatic mutation status of these patients was not reported. These findings indicated that tyr371 is a hotspot for mutations associated with JMML.
Niemeyer et al. (2010) identified a heterozygous Y371H germline mutation in 7 of 21 unrelated patients with JMML. Leukemic cells from these patients showed homozygosity for the mutation, consistent with CBL functioning as a tumor suppressor gene. Two of the patients developed juvenile xanthogranulomas, and 3 had developmental delay. Family history was available from 2 patients. One had maternal relatives who died from progressive JMML and a maternal grandmother who had infantile leukemia that resolved spontaneously. The second had 2 male relatives who had died from JMML, one of whom developed small vessel vasculitis before his death. Leukemic cells from patients with the Y371H mutation showed GM-CSF hypersensitivity. In vitro studies in mouse cells with reduced Cbl expression showed that the mutant protein resulted in cytokine-independent proliferation and hypersensitivity to growth factors, associated with constitutive phosphorylation of several proteins. The mutant Y371H protein also showed a defect in E3 ligase function, supporting a role for tyr371 in maintaining the integrity of the alpha-helical structure of the linker region, which has a critical role in substrate specificity. Niemeyer et al. (2010) reported 3 additional heterozygous mutations affecting the tyr371 residue (see, e.g., 165360.0009).
In leukemic cells derived from 2 unrelated girls with Noonan syndrome-like disorder who developed early-onset juvenile myelomonocytic leukemia (NSLL; 613563), Niemeyer et al. (2010) identified a homozygous A-to-G transition (1228-2A-G) in the CBL gene, resulting in a splicing defect and the deletion of exon 9. The resultant protein was predicted to lack essential regions of the linker and RING finger domains. One of the patients was found to carry the heterozygous mutation in her germline and showed poor growth and developmental delay; nonleukemic tissue was not available from the second patient, who died of leukemia.
In a 1-year-old girl with Noonan syndrome-like disorder and early-onset JMML (NSLL; 613563), Niemeyer et al. (2010) identified a heterozygous germline mutation in the CBL gene, resulting in a cys384-to-arg (C384R) substitution. Leukemic cells were homozygous for the mutation. She had frontal bossing, downslanting palpebral fissures, ptosis, hypertelorism, and a low nasal bridge. She inherited the C384R mutation from her father, who also had ptosis. Two additional patients with JMML had homozygous C384R mutations in leukemic cells, but normal tissue was not available for analysis.
In a male infant with Noonan syndrome-like disorder and early-onset JMML (NSLL; 613563), Niemeyer et al. (2010) identified a heterozygous germline mutation in the CBL gene, resulting in a cys396-to-arg (C396R) substitution. Leukemic cells were homozygous for the mutation. The patient had developmental delay and hearing loss, but also developed optic atrophy, hypertension, and cardiomyopathy, consistent with vascular pathology. Niemeyer et al. (2010) postulated that the CBL mutation contributed to dysregulated lymphocyte signaling and vasculitis.
Juvenile Myelomonocytic Leukemia
In 3 affected members of a family with juvenile myelomonocytic leukemia (JMML; 607785), Pathak et al. (2015) identified a germline heterozygous Y371C mutation in the CBL gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was also present in 4 family members without JMML, consistent with incomplete penetrance. Structural modeling predicted that the mutation would abrogate the ability of the mutant protein to adopt a conformation that would permit protein ubiquitination. Functional studies were not performed.
Noonan Syndrome-like Disorder and Early-Onset Juvenile Myelomonocytic Leukemia
In a male infant with Noonan syndrome-like disorder and early-onset JMML (NSLL; 613563), Niemeyer et al. (2010) identified a heterozygous germline mutation in the CBL gene, resulting in a tyr371-to-cys (Y371C) substitution. Leukemic cells were homozygous for the mutation. He had cafe-au-lait spots, cryptorchidism, developmental delay, hearing loss, optic atrophy, hypertension, and cardiomyopathy. Niemeyer et al. (2010) studied the effects of the Y371H mutation (165360.0005) and noted that their findings support a role for tyr371 in maintaining the integrity of the alpha-helical structure of the linker region, which has a critical role in substrate specificity.
This variant is classified as a variant of unknown significance because its contribution to developmental and epileptic encephalopathy (see 308350) has not been confirmed.
In an Indian girl (patient 6) with severe tonic epilepsy, developmental delay, and microcephaly, Martin et al. (2014) identified a de novo heterozygous G-to-A transition in intron 8 of the CBL gene (c.1228-1G-A, NM_005188), resulting in the skipping of exon 9 and the in-frame deletion of 68 residues. The mutation was found by whole-genome sequencing and confirmed by Sanger sequencing. Martin et al. (2014) noted that exon 9 encodes the C-terminal part of the RING finger domain that is responsible for ubiquitin ligase activity, and suggested that the mutation may ablate ubiquitin ligase activity, causing increased Ras/MAPK signaling. The patient had extensive hypopigmented skin patches, congenital heart defects, severe developmental delay, and microcephaly, but a clinical diagnosis of neurocardiofaciocutaneous syndrome was not considered likely.
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