CBLB

Inheritance Pattern: AR

Disease ID:MONDO:0957388

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0957388

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0957388

Submitter: ClinGen

*CBLB* was first reported in relation to multisystem autoimmune infantile-onset disease 3 (PMID: 36006710). At least 3 unique variants (2 missense, 1 nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Experimental evidence includes biochemical function (PMID: 20624942, 21248250, 11526404, 36165179), protein interaction ( PMID: 19190244, 25560411), evidence of functional alteration (PMID 36006710), mouse model (PMID: 36006710, 10646609, 10646608, 12118252, 17618294), , and mouse rescue model (PMID 12118252, 17618294). Variants in this gene have been reported in at least 3 probands in 1 publication (PMID: 36006710). Genetic variants in CBLB have been reported to be associated autosomal recessive human immune dysregulation-first reported in relation to multisystem autoimmune infantile-onset disease 3 (PMID: 36006710). CBLB encodes CBL-B, a RING-type E3 ubiquitin ligase highly expressed in immune cells. It ubiquitinates receptor-proximal signaling proteins downstream of the TCR, BCR, CD28, and FcεRI, thereby raising the threshold for lymphocyte activation, promoting T-cell anergy, and maintaining peripheral tolerance. A key non-proteolytic action is ubiquitination of the PI3K p85 subunit, uncoupling TCR/CD28 signaling; CBL-B is itself stabilized by CTLA-4 engagement and degraded upon CD28 costimulation. It shares substrates partly redundantly with its paralog CBL. In summary, mechanistically, CBL-B is a negative regulator of lymphocyte activation and peripheral tolerance. In the Janssen et al. (PMID: 36006710) report, three unrelated children with early-onset autoimmunity (one also with chronic urticaria) carrying distinct biallelic CBLB variants have been described: p.R496X (abolished protein), p.C464W (preserved protein), and p.H285L (SH2 domain, reduced expression). Patient T cells had excessive proliferation to anti-CD3, and p.H285L effector T cells were resistant to Treg suppression establishing CBL-B deficiency as a cause of human immune dysregulation. A knock-in mouse (Cblb H257L, orthologous to patient p.H285L) reproduced T/B-cell hyperproliferation, Treg-resistant effector T cells, mast-cell hyperactivation after FcεRI cross-linking, and exaggerated IgE-mediated anaphylaxis providing a strong genotype-matched model concordance. Experimental data demonstrates that the E3 ligase catalytic activity is essential for CBL-B's negative regulation of T cells in vivo, and that Cblb−/− effector T cells are intrinsically resistant to Treg suppression. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.​