Affinage

CBLC

E3 ubiquitin-protein ligase CBL-C · UniProt Q9ULV8

Length
474 aa
Mass
52.5 kDa
Annotated
2026-06-09
100 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CBLC is a RING-finger E3 ubiquitin ligase of the CBL family that regulates receptor tyrosine kinase signaling and protein turnover through substrate-selective ubiquitination, generally acting as a negative regulator of cell proliferation (PMID:10571044, PMID:19414407). Its catalytic output is governed by an N-terminal EF-hand/SH2 module that autoinhibits the enzyme; Src-mediated phosphorylation of Tyr-341, or a phosphomimetic substitution, relieves this inhibition by lowering affinity for the E2 enzyme UbcH5b and accelerating ubiquitin-transfer turnover (PMID:20525694), and its TKB domain engages phosphotyrosine substrates with a constrained structural flexibility that distinguishes it from other CBL members (PMID:22888118). The chain architecture CBLC assembles dictates whether substrates are degraded or protected: it targets activated Src for lysosomal degradation (PMID:14661060) and routes ABI1 and cortactin to the proteasome (PMID:36043996, PMID:38743987), yet builds non-canonical K6/K11-linked chains on activated EGFR that promote recycling and sustained ERK signaling rather than lysosomal degradation, in opposition to canonical CBL (PMID:29945960), and conjugates protective monoubiquitin and K11/K63 chains that stabilize Aurora kinase A and METTL1 against degradative ubiquitination (PMID:35149839, PMID:42217705). Its activity is further tuned by partners including the HECT ligase AIP4/ITCH and the LIM protein Hic-5, which enhances CBLC-mediated EGFR ubiquitination (PMID:12226085, PMID:23145173), and CBLC also maintains Golgi ribbon network organization in an E3-activity- and SRC-dependent manner (PMID:26393512). RING-finger loss-of-function mutations found in human and mouse tumors abolish EGFR ubiquitination and act dominant-negatively to promote transformation (PMID:31260484).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 Medium

    Establishing CBLC as a distinct CBL family member with a defined domain architecture and direct kinase-binding capacity set the structural premise for all subsequent mechanistic work.

    Evidence Molecular cloning and binding assays identifying a 52 kDa protein with phosphotyrosine-binding domain, RING finger, and proline-rich region that binds EGFR and Fyn

    PMID:10571044

    Open questions at the time
    • No enzymatic activity demonstrated
    • Functional consequence of EGFR/Fyn binding undefined
  2. 2002 High

    Linking CBLC to the HECT ligase AIP4/ITCH and showing cooperative EGFR downregulation placed CBLC within receptor tyrosine kinase signaling control and identified a functional partnership.

    Evidence Yeast two-hybrid, GST pull-down, reciprocal co-IP, colocalization, and EGFR ubiquitination assays

    PMID:12226085

    Open questions at the time
    • Direct CBLC ubiquitination of EGFR vs. AIP4 contribution not separated
    • Chain linkage type not determined
  3. 2004 High

    Demonstrating that CBLC ubiquitinates activated Src for lysosomal degradation and reverses v-Src transformation established its anti-oncogenic, RING-dependent catalytic function with phospho-substrate selectivity.

    Evidence In vitro reconstituted ubiquitination with UbcH5, RING mutant controls, degradation assay, and NIH3T3 transformation reversion

    PMID:14661060

    Open questions at the time
    • Lysosomal targeting mechanism not detailed
    • Chain linkage type unresolved
  4. 2010 High

    Resolving the autoinhibition/activation switch explained how CBLC catalysis is gated by Src phosphorylation at Tyr-341 through modulation of E2 affinity.

    Evidence In vitro ubiquitination, Y341 mutagenesis/phosphomimetic, and UbcH5b binding affinity measurements

    PMID:20525694

    Open questions at the time
    • Structural basis of the EF-hand/SH2 autoinhibited state not solved
    • In-cell kinetics of the switch not measured
  5. 2012 High

    The TKB domain crystal structure showed that restricted flexibility relative to CBL tunes phosphopeptide binding, providing a structural rationale for CBLC's distinct substrate engagement.

    Evidence X-ray crystallography with flexibility-altering mutagenesis and phosphopeptide binding assays

    PMID:22888118

    Open questions at the time
    • No co-structure with a physiological substrate
    • Functional consequence of flexibility in cells untested
  6. 2012 Medium

    Identifying Hic-5 as a RING-binding cofactor that boosts CBLC activity revealed a novel mode of E3 regulation by a LIM zinc-coordinating domain.

    Evidence Co-IP, domain mapping, and EGFR ubiquitination assays

    PMID:23145173

    Open questions at the time
    • Mechanism by which LIM2 enhances catalysis not defined
    • Physiological context of Hic-5/CBLC cooperation untested in vivo
  7. 2015 High

    Connecting CBLC to PARP inhibitor sensitivity and HR repair, and to Golgi ribbon maintenance, broadened its cellular roles beyond RTK signaling.

    Evidence RNAi screen with olaparib viability and HR assays; image-based knockdown with microscopy, E3-mutant rescue, and SRC inhibitor treatment

    PMID:25883215 PMID:26393512

    Open questions at the time
    • Molecular substrate linking CBLC to HR repair unidentified
    • Golgi substrate of CBLC ubiquitination not identified
  8. 2018 High

    Determining that CBLC builds K6/K11 chains on activated EGFR to drive recycling rather than degradation reversed the expectation of CBL-like negative regulation and explained its pro-oncogenic role in lung cancer.

    Evidence Mass-spectrometry ubiquitin linkage analysis, co-IP, EGFR trafficking assays, knockdown/overexpression, and xenografts

    PMID:29945960

    Open questions at the time
    • Reconciliation with earlier anti-oncogenic findings context-dependent and unresolved
    • Reader/effector decoding K6/K11 chains on EGFR not identified
  9. 2019 Medium

    Showing that tumor-derived RING mutants are catalytically dead and dominant-negative clarified how CBLC loss-of-function contributes to transformation by blocking other CBL proteins.

    Evidence Ubiquitination assay, co-IP, and NIH 3T3 transformation assay with SV40 Large T

    PMID:31260484

    Open questions at the time
    • Frequency and clinical impact of these mutations not established
    • Competition mechanism with wild-type CBL not quantified
  10. 2022 High

    Identifying AURKA and cortactin as substrates demonstrated that CBLC can either protectively stabilize (AURKA via K11/K63) or proteasomally degrade (cortactin) substrates, controlling mitosis and cell motility respectively.

    Evidence IP-MS, ubiquitin linkage typing, cycloheximide chase, cell synchronization/FACS, xenografts; co-IP, colocalization, and migration/invasion rescue assays

    PMID:35149839 PMID:36043996

    Open questions at the time
    • Determinants selecting protective vs. degradative chains on different substrates unknown
    • Whether AURKA and CTTN regulation co-occur in the same cells untested
  11. 2024 Medium

    Establishing ABI1 as a degradative substrate linked CBLC to ERK pathway activation and a pro-tumorigenic role in colorectal cancer.

    Evidence Ubiquitination assay, co-IP, ERK readout, rescue with ABI1 overexpression, and xenograft/metastasis models

    PMID:38743987

    Open questions at the time
    • Direct vs. indirect ERK activation not dissected
    • Chain linkage on ABI1 not typed
  12. 2026 Medium

    Showing CBLC stabilizes METTL1 to enhance m7G modification of ESRRA mRNA extended its substrate repertoire into RNA-modification machinery and endometrial cancer.

    Evidence Ubiquitination assay, co-IP, m7G and mRNA stability assays, rescue experiments, and transcriptomics

    PMID:42217705

    Open questions at the time
    • Chain linkage stabilizing METTL1 not fully typed
    • Generality of CBLC-METTL1 axis beyond endometrial cancer untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • What governs CBLC's context-dependent choice between degradative and protective/recycling ubiquitin chains on different substrates, and how this dictates its opposing tumor-suppressive versus pro-oncogenic outcomes, remains unresolved.
  • No unifying model for substrate-specific chain-type selection
  • Tissue determinants of anti- vs. pro-oncogenic behavior undefined
  • Structure of full-length CBLC-substrate-E2 complex not solved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 4 GO:0016874 ligase activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2 R-HSA-1640170 Cell Cycle 1
Partners
ABI1AIP4AURKACTTNEGFRFYNMETTL1SRC

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 CBLC (Cbl-c) protein was identified as a novel CBL family member encoding a 52 kDa protein with a phosphotyrosine-binding domain, RING finger, and proline-rich region. The Cbl-c protein was shown to bind the EGF receptor and Fyn tyrosine kinase. Molecular cloning, co-immunoprecipitation/binding assay Gene Medium 10571044
2001 Mouse Cblc/Cbl3 gene was cloned; it comprises 12 exons and encodes a 496 amino acid protein sharing 67% identity with the human ortholog and 70% identity with mouse CBL over conserved SH2 and RING finger domains. Cblc mRNA is expressed ubiquitously in embryo and adult tissues. Molecular cloning, expression analysis Biochemical and biophysical research communications Low 11162497
2002 CBLC interacts with the HECT-domain E3 ubiquitin ligase AIP4/ITCH (and its C. elegans counterpart WWP1) via CBLC's proline-rich region and the WW domains of AIP4. This interaction was confirmed by GST pull-down, co-immunoprecipitation, and colocalization. CBLC and AIP4 both become tyrosine-phosphorylated upon EGF stimulation. Overexpression of CBLC increased EGFR ubiquitination, and coexpression of WW domains of AIP4 exerted a dominant-negative effect on EGFR ubiquitination. Coexpression of CBLC and AIP4 together downregulated EGFR signaling. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, colocalization, ubiquitination assay The Journal of biological chemistry High 12226085
2004 CBLC (Cbl-c) specifically targets activated Src (phosphorylated at Tyr419) for ubiquitination and degradation via a lysosome-dependent pathway. The TKB domain and RING finger of CBLC are required for its anti-oncogenic activity. Wild-type CBLC together with UbcH5 induced ubiquitination of Src in vitro, while a RING finger mutant did not. Non-phosphorylated Src was not ubiquitinated by CBLC. CBLC suppressed v-Src-induced transformation and caused reversion of the morphological phenotype in NIH3T3 cells, distinct from the mechanism of Cbl and Cbl-b. In vitro ubiquitination assay with UbcH5, RING finger mutagenesis, cell transformation assay, protein degradation assay Oncogene High 14661060
2009 Transgenic mice expressing CBLC in the mammary gland (MMTV-CBLC) showed reduced number and length of ducts during mammary gland development, supporting CBLC's role as a negative regulator of cell proliferation in epithelial tissues. Transgenic mouse model, in vivo mammary gland morphology assessment In vivo (Athens, Greece) Low 19414407
2010 The N-terminus of Cbl-c (specifically the EF-hand and SH2 domains) inhibits its E3 ubiquitin ligase activity. Phosphorylation of a critical tyrosine residue (Tyr-341) in the linker region by Src kinase, or a phosphomimetic Y341E mutation, relieves this inhibition by decreasing affinity for the E2 enzyme UbcH5b. Reduced E2 affinity leads to more rapid turnover of bound UbcH5b and increased E3 ligase activity. In vitro ubiquitination assay, site-directed mutagenesis, E2-binding affinity measurement The Journal of biological chemistry High 20525694
2012 CBLC interacts with Hic-5 (Hydrogen peroxide Induced Construct 5) through a novel interaction between the RING finger of CBLC and the LIM2 domain of Hic-5, mediated by specific zinc-coordinating complexes. Binding of Hic-5 to CBLC increases CBLC ubiquitin ligase activity (after Src-mediated activation) and enhances CBLC-mediated ubiquitination of EGFR. This is the first example of a LIM zinc-coordinating domain enhancing RING finger E3 ligase activity. Co-immunoprecipitation, ubiquitination assay, domain mapping PloS one Medium 23145173
2012 Crystal structure of the tyrosine kinase binding (TKB) domain of Cbl-c/Cbl-3 revealed that, compared to Cbl TKB, the Cbl-c TKB domain shows restricted structural flexibility upon phosphopeptide binding. A mutation in Cbl-c TKB that increased structural flexibility enhanced binding to target phosphoproteins, indicating that structural flexibility regulates phosphopeptide-binding activity. X-ray crystallography, phosphopeptide binding assay, mutagenesis Journal of biochemistry High 22888118
2015 RNAi screening identified CBLC as a modifier of PARP inhibitor (olaparib) sensitivity. Silencing of CBLC caused increased sensitivity to olaparib in breast cancer cell lines, with defective homologous recombination (HR) DNA repair identified as the likely mechanism. RNAi screen, cell viability assay, HR repair assay Oncotarget Medium 25883215
2015 Depletion of CBLC specifically induces Golgi fragmentation (disruption of Golgi ribbon/network organization) without significantly affecting Golgi stack structure. CBLC partially localizes to Golgi membranes, and this localization is enhanced after SRC kinase activation. Inhibition of SRC reverts the Golgi fragmentation caused by CBLC depletion, indicating interplay between CBLC and SRC at the Golgi. CBLC's regulation of Golgi network organization requires its ubiquitin ligase activity. Depletion of the close homologues CBL and CBLB did not induce visible Golgi defects. RNAi knockdown, fluorescence and electron microscopy, Golgi morphology quantification, SRC inhibitor treatment, E3 mutant rescue PloS one High 26393512
2018 CBLC is epigenetically upregulated (by promoter demethylation) in non-small cell lung cancer. CBLC competes with CBL for EGFR binding and, unlike CBL-mediated K63-linked ubiquitination promoting lysosomal degradation, CBLC ubiquitinates activated EGFR (aEGFR) via K6 and K11 polyubiquitin linkages, which promotes recycling of aEGFR back to the plasma membrane or trafficking to the nucleus rather than lysosomal degradation, thereby sustaining EGFR activation and downstream ERK1/2 signaling. CBLC depletion/overexpression, ubiquitin linkage analysis (mass spectrometry), co-immunoprecipitation, EGFR trafficking assay, xenograft model Cancer research High 29945960
2019 Loss-of-function mutations in the RING finger domain of CBLC (identified in a mouse mammary tumor and in human solid tumors) abolish CBLC-mediated ubiquitination of activated EGFR and allow the mutant protein to act in a dominant-negative fashion by binding EGFR and preventing recruitment and action of wild-type CBL family proteins. A CBLC RING-finger deletion mutant enhanced NIH 3T3 cell transformation when combined with SV40 Large T antigen. Ubiquitination assay, co-immunoprecipitation, NIH 3T3 transformation assay, genomic/cDNA sequence analysis PloS one Medium 31260484
2022 CBLC interacts with AURKA (Aurora kinase A) through AURKA's kinase domain, as determined by immunoprecipitation and mass spectrometry. CBLC stabilizes AURKA by conjugating monoubiquitination and K11/K63-linked polyubiquitination, protecting it from degrading K11/K48 polyubiquitination. CBLC depletion decreased AURKA half-life and delayed its accumulation/activation during mitotic entry, reducing the mitotic population and increasing apoptosis in lung adenocarcinoma cells. Immunoprecipitation/mass spectrometry, ubiquitin linkage analysis, cycloheximide chase, cell synchronization/FACS, xenograft model Oncogene High 35149839
2022 CBLC interacts with CTTN (cortactin) in the cytoplasm, as shown by co-immunoprecipitation and immunofluorescence co-localization. CBLC promotes degradation of CTTN through the ubiquitin-proteasome pathway, and this activity inhibits breast cancer cell proliferation, migration, and invasion. Overexpression of CTTN partially rescues the inhibitory effect of CBLC. Co-immunoprecipitation, immunofluorescence co-localization, ubiquitination/proteasome assay, cell proliferation/migration/invasion assays Journal of receptor and signal transduction research Medium 36043996
2024 CBLC ubiquitinates ABI1 (Abelson interactor protein 1), promoting its proteasomal degradation. CBLC-mediated ABI1 degradation activates the ERK signaling pathway. ABI1 overexpression abolishes the pro-tumorigenic effects of CBLC in colorectal cancer cells. CBLC also promoted tumor growth and metastasis in xenograft models. Ubiquitination assay, co-immunoprecipitation, western blot, cell proliferation/migration/invasion assays, xenograft and lung metastasis models Translational oncology Medium 38743987
2026 CBLC ubiquitinates METTL1 (tRNA guanine-N7-methyltransferase), stabilizing it against proteasomal degradation. Stabilized METTL1 enhances N7-methylguanosine (m7G) modification of ESRRA mRNA, increasing ESRRA stability and expression, which mediates CBLC's pro-tumorigenic effects in endometrial cancer. Ubiquitination assay, co-immunoprecipitation, m7G methylation assay, mRNA stability assay, functional rescue experiments, single-cell and bulk transcriptomics International journal of biological macromolecules Medium 42217705

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nature genetics 304 16311595
2011 Combined methylmalonic acidemia and homocystinuria, cblC type. I. Clinical presentations, diagnosis and management. Journal of inherited metabolic disease 179 21748409
2014 Clinical presentation and outcome in a series of 88 patients with the cblC defect. Journal of inherited metabolic disease 136 24599607
2006 Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations. Molecular genetics and metabolism 115 16714133
2009 Processing of alkylcobalamins in mammalian cells: A role for the MMACHC (cblC) gene product. Molecular genetics and metabolism 102 19447654
2007 Spectrum of MMACHC mutations in Italian and Portuguese patients with combined methylmalonic aciduria and homocystinuria, cblC type. Molecular genetics and metabolism 82 18164228
2007 Hemolytic uremic syndrome (HUS) secondary to cobalamin C (cblC) disorder. Pediatric nephrology (Berlin, Germany) 79 17874135
2009 Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC). Human mutation 78 19760748
2002 Interaction between two ubiquitin-protein isopeptide ligases of different classes, CBLC and AIP4/ITCH. The Journal of biological chemistry 73 12226085
2010 Clinical, biochemical, and molecular analysis of combined methylmalonic acidemia and hyperhomocysteinemia (cblC type) in China. Journal of inherited metabolic disease 71 20924684
2018 APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients. Nature communications 70 29302025
2007 Late-onset combined homocystinuria and methylmalonic aciduria (cblC) and neuropsychiatric disturbance. American journal of medical genetics. Part A 54 17853453
1999 Molecular cloning and characterization of a novel cbl-family gene, cbl-c. Gene 54 10571044
2009 High prevalence of structural heart disease in children with cblC-type methylmalonic aciduria and homocystinuria. Molecular genetics and metabolism 52 19767224
2005 Late-onset thrombocytic microangiopathy caused by cblC disease: association with a factor H mutation. American journal of kidney diseases : the official journal of the National Kidney Foundation 52 15754282
2004 Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation. Oncogene 52 14661060
2015 Clinical presentation, gene analysis and outcomes in young patients with early-treated combined methylmalonic acidemia and homocysteinemia (cblC type) in Shandong province, China. Brain & development 51 26563984
2018 Upregulation of E3 Ubiquitin Ligase CBLC Enhances EGFR Dysregulation and Signaling in Lung Adenocarcinoma. Cancer research 49 29945960
2010 Thermolability of mutant MMACHC protein in the vitamin B12-responsive cblC disorder. Molecular genetics and metabolism 48 20219402
2009 Mechanism of vitamin B12-responsiveness in cblC methylmalonic aciduria with homocystinuria. Molecular genetics and metabolism 45 19700356
2015 Pathogenic mutations differentially affect the catalytic activities of the human B12-processing chaperone CblC and increase futile redox cycling. The Journal of biological chemistry 34 25809485
2013 The C-terminal domain of CblD interacts with CblC and influences intracellular cobalamin partitioning. Biochimie 34 23415655
2010 The N terminus of Cbl-c regulates ubiquitin ligase activity by modulating affinity for the ubiquitin-conjugating enzyme. The Journal of biological chemistry 34 20525694
2012 A clinical and gene analysis of late-onset combined methylmalonic aciduria and homocystinuria, cblC type, in China. Journal of the neurological sciences 33 22560872
2022 Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists. Orphanet journal of rare diseases 31 35109910
2018 Molecular genetic characterization of cblC defects in 126 pedigrees and prenatal genetic diagnosis of pedigrees with combined methylmalonic aciduria and homocystinuria. BMC medical genetics 31 30157807
2015 The proteome of cblC defect: in vivo elucidation of altered cellular pathways in humans. Journal of inherited metabolic disease 31 25585586
2017 Antivitamin B12 Inhibition of the Human B12 -Processing Enzyme CblC: Crystal Structure of an Inactive Ternary Complex with Glutathione as the Cosubstrate. Angewandte Chemie (International ed. in English) 30 28544088
2013 Interaction between methionine synthase isoforms and MMACHC: characterization in cblG-variant, cblG and cblC inherited causes of megaloblastic anaemia. Human molecular genetics 26 23825108
2022 The Follow-Up of Chinese Patients in cblC Type Methylmalonic Acidemia Identified Through Expanded Newborn Screening. Frontiers in genetics 25 35242167
2017 Coordination chemistry controls the thiol oxidase activity of the B12-trafficking protein CblC. The Journal of biological chemistry 22 28442570
2010 Early onset methylmalonic aciduria and homocystinuria cblC type with demyelinating neuropathy. Pediatric neurology 21 20610126
2024 Late-onset methylmalonic acidemia and homocysteinemia (cblC disease): systematic review. Orphanet journal of rare diseases 19 38245797
2020 The human B12 trafficking protein CblC processes nitrocobalamin. The Journal of biological chemistry 19 32457044
2020 Mouse models to study the pathophysiology of combined methylmalonic acidemia and homocystinuria, cblC type. Developmental biology 19 32941884
2015 Whole Exome Sequencing Identifies an Adult-Onset Case of Methylmalonic Aciduria and Homocystinuria Type C (cblC) with Non-Syndromic Bull's Eye Maculopathy. Ophthalmic genetics 19 25687216
2012 Cbl-c ubiquitin ligase activity is increased via the interaction of its RING finger domain with a LIM domain of the paxillin homolog, Hic 5. PloS one 19 23145173
2017 Atypical hemolytic uremic syndrome induced by CblC subtype of methylmalonic academia: A case report and literature review. Medicine 18 29068997
2007 Marfanoid features in a child with combined methylmalonic aciduria and homocystinuria (CblC type). Journal of inherited metabolic disease 18 17768669
2018 Hydrocephalus in cblC type methylmalonic acidemia. Metabolic brain disease 17 30564975
2022 Stabilization of AURKA by the E3 ubiquitin ligase CBLC in lung adenocarcinoma. Oncogene 16 35149839
2015 Complementary genetic screens identify the E3 ubiquitin ligase CBLC, as a modifier of PARP inhibitor sensitivity. Oncotarget 16 25883215
2022 Late-onset cblC deficiency around puberty: a retrospective study of the clinical characteristics, diagnosis, and treatment. Orphanet journal of rare diseases 15 36056359
2021 PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations. Clinical epigenetics 15 34215320
2010 Treatment of cobalamin C (cblC) deficiency during pregnancy. Journal of inherited metabolic disease 15 20830523
2013 Novel Deletion Mutation Identified in a Patient with Late-Onset Combined Methylmalonic Acidemia and Homocystinuria, cblC Type. JIMD reports 14 23580368
2014 First Chinese case of successful pregnancy with combined methylmalonic aciduria and homocystinuria, cblC type. Brain & development 13 24974159
2022 Epimutations in both the TESK2 and MMACHC promoters in the Epi-cblC inherited disorder of intracellular metabolism of vitamin B12. Clinical epigenetics 12 35440018
2020 Thiolatocobalamins repair the activity of pathogenic variants of the human cobalamin processing enzyme CblC. Biochimie 12 33190793
2019 Loss of function Cbl-c mutations in solid tumors. PloS one 12 31260484
2012 Structural flexibility regulates phosphopeptide-binding activity of the tyrosine kinase binding domain of Cbl-c. Journal of biochemistry 12 22888118
2011 Combined methylmalonic aciduria and homocystinuria cblC type of a Taiwanese infant with c.609G>A and C.567dupT mutations in the MMACHC gene. Pediatrics and neonatology 12 21835369
2010 Different altered pattern expression of genes related to apoptosis in isolated methylmalonic aciduria cblB type and combined with homocystinuria cblC type. Biochimica et biophysica acta 12 20696242
2022 Intracellular processing of vitamin B12 by MMACHC (CblC). Vitamins and hormones 10 35337623
2019 Noninvasive prenatal diagnosis of cobalamin C (cblC) deficiency through target region sequencing of cell-free DNA in maternal plasma. Prenatal diagnosis 10 31697851
2023 Variable phenotypes and outcomes associated with the MMACHC c.482G > A mutation: follow-up in a large CblC disease cohort. World journal of pediatrics : WJP 8 38070096
2021 Epimutation of MMACHC compound to a genetic mutation in cblC cases. Molecular genetics & genomic medicine 8 33982424
2021 Clinical features and outcomes of patients with cblC type methylmalonic acidemia carrying gene c.609G>A mutation. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences 8 34704411
2020 Chlorocob(II)alamin Formation Which Enhances the Thiol Oxidase Activity of the B12-Trafficking Protein CblC. Inorganic chemistry 8 33074687
2017 Optical coherence tomography morphology and evolution in cblC disease-related maculopathy in a case series of very young patients. Acta ophthalmologica 8 28481040
2022 Noninvasive Prenatal Testing of Methylmalonic Acidemia cblC Type Using the cSMART Assay for MMACHC Gene Mutations. Frontiers in genetics 7 35069678
2015 The Ubiquitin Ligase CBLC Maintains the Network Organization of the Golgi Apparatus. PloS one 7 26393512
2023 Abnormal chondrocyte development in a zebrafish model of cblC syndrome restored by an MMACHC cobalamin binding mutant. Differentiation; research in biological diversity 6 37167860
2022 The human B12 trafficking chaperones: CblA, ATR, CblC and CblD. Methods in enzymology 6 35589192
2022 Investigation on a MMACHC mutant from cblC disease: The c.394C>T variant. Biochimica et biophysica acta. Proteins and proteomics 6 35618206
2022 Efficacy and pharmacokinetics of betaine in CBS and cblC deficiencies: a cross-over randomized controlled trial. Orphanet journal of rare diseases 6 36376887
2009 Abnormal mammary gland development in MMTV-CBLC transgenic mouse. In vivo (Athens, Greece) 6 19414407
2023 Would, early, versus late hydroxocobalamin dose intensification treatment, prevent cognitive decline, macular degeneration and ocular disease, in 5 patients with early-onset cblC deficiency? Molecular genetics and metabolism 5 37604084
2022 CBLC inhibits the proliferation and metastasis of breast cancer cells via ubiquitination and degradation of CTTN. Journal of receptor and signal transduction research 5 36043996
2020 Generation of a Human iPSC line (SDQLCHi021-A) from a patient with methylmalonic acidemia cblC type carrying compound heterozygous mutations in MMAHC gene. Stem cell research 5 32058304
2020 Analysis of fibroblasts from patients with cblC and cblG genetic defects of cobalamin metabolism reveals global dysregulation of alternative splicing. Human molecular genetics 5 32068834
2015 Genetic analysis of four cases of methylmalonic aciduria and homocystinuria, cblC type#. International journal of clinical and experimental pathology 5 26464686
2001 Characterization of the mouse Cblc/Cbl3 gene. Biochemical and biophysical research communications 5 11162497
1991 Metabolic cooperation among cell lines from patients with inborn errors of vitamin B12 metabolism: differential response of cblC and cblD. Clinical and investigative medicine. Medecine clinique et experimentale 5 1676355
2022 Acute Lymphoblastic Leukemia in Combined Methylmalonic Acidemia and Homocysteinemia (cblC Type): A Case Report and Literature Review. Frontiers in genetics 4 35495149
1992 Clinical and biochemical observations in a patient with combined Pompe disease and cblC mutation. European journal of pediatrics 4 1537354
2024 The MMACHC variant c.158T>C: Mild clinical and biochemical phenotypes and marked hydroxocobalamin response in cblC patients. Molecular genetics and metabolism 3 38387306
2022 Antivitamins B12: Synthesis and application as inhibitory ligand of the B12-tailoring enzyme CblC. Methods in enzymology 3 35589193
2021 Preimplantation Genetic Testing for Rare Inherited Disease of MMA-CblC: an Unaffected Live Birth. Reproductive sciences (Thousand Oaks, Calif.) 3 34076870
2017 Neuropsychological implications of Cobalamin C (CblC) disease in Hispanic children detected through newborn screening. Applied neuropsychology. Child 3 28071971
2010 [Analysis of clinical features and gene mutations in two Chinese pedigrees with late-onset methylmalonic acidemia, cblC type]. Zhonghua er ke za zhi = Chinese journal of pediatrics 3 21055272
2025 Variable phenotypes and outcomes associated with the MMACHC c.1A>G variant in Chinese patients with combined methylmalonic acidemia and homocystinuria cblC type. Molecular genetics and metabolism 2 40544542
2023 Case report: An asymptomatic mother with an inborn error of cobalamin metabolism (cblC) detected through high homocysteine levels during prenatal diagnosis. Frontiers in nutrition 2 37252234
2022 [Factors affecting phenotypes in the patients with MMACHC gene c.609G>A homozygous variant cblC type methylmalonic acidemia combined with homocysteinuria]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 2 35773756
2019 [Construction of a mouse model of cblC type methylmalonic acidemia with W203X mutation based on the CRISPR/Cas9 technology]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 2 31416510
2025 Accelerating the diagnosis of Chinese cblC type MMA patients by multiplex PCR sequencing method. Pediatric research 1 39815091
2025 Missense mutations in MMACHC protein from cblC disease affect its conformational stability and vitamin B12-binding activity: The example of R161Q mutation. Molecular genetics and metabolism 1 40441036
2025 Long-term outcome of CblC deficiency complicated with pulmonary hypertension. Orphanet journal of rare diseases 1 40468431
2024 Adult-onset combined methylmalonic acidemia and hyperhomocysteinemia, cblC type with aortic dissection and acute kidney injury: a case report. BMC nephrology 1 38178022
2022 [Genetic variant analysis and prenatal diagnosis for Chinese pedigrees affected with cblC methylmalonic acidemia]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 36184083
2022 A teenager with combined methylmalonic aciduria and homocystinuria (CblC type) presenting with neurological symptoms and congenital heart diseases: a case report. Neurocase 1 36219783
2026 CBLC-mediated ubiquitination stabilizes METTL1, enhances N7-methylguanosine modification of ESRRA, and promotes the progression of endometrial cancer. International journal of biological macromolecules 0 42217705
2025 A Noncatalytic Cysteine Residue Modulates Cobalamin Reactivity in the Human B12 Processing Enzyme CblC. Biochemistry 0 39862167
2025 Modulation of conformational features and oligomerization of MMACHC by cobalamin variants: impact of the R161Q mutation in cblC disease. European biophysics journal : EBJ 0 40576712
2025 Analysis of hydroxocobalamin dosage in patients with CblC deficiency. Orphanet journal of rare diseases 0 40841656
2024 CBLC promotes the development of colorectal cancer by promoting ABI1 degradation to activate the ERK signaling pathway. Translational oncology 0 38743987
2024 Evaluation of the clinical, biochemical, and molecular spectrum of Cobalamin C (CblC) defect in 33 patients from Pakistan. Scandinavian journal of clinical and laboratory investigation 0 39225018
2024 [Analysis of the regional distribution differences of common variations of the MMACHC gene in cblC methylmalonic acidemia patients]. Zhonghua er ke za zhi = Chinese journal of pediatrics 0 39429080
2024 A case series of Cypriot patients with CblC defect: Clinical, biochemical and molecular characteristics. Molecular genetics and metabolism reports 0 39584041
2023 Abnormal chondrocyte intercalation in a zebrafish model of cblC syndrome restored by an MMACHC cobalamin binding mutant. bioRxiv : the preprint server for biology 0 36711998

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