Disease relevance of CBLB

• Together with the fact that CBLB is consistently found in blast cells from acute leukemias and in peripheral blood mononuclear cells, this suggests that CBLB has a role in tyrosine kinase-regulated signaling pathways in many hematolymphoid cells [1].
• We screened coding regions of the human CBLB gene for mutations in a panel of individuals affected with several autoimmune diseases [2].
• Recent studies of an animal model of T1D, the Komeda diabetes-prone rat, have demonstrated that the Casitas-B-lineage lymphoma b (cblb) gene is a major susceptibility gene in the development of diabetes and other autoimmune features of this rat [2].
• The CBLB gene and Graves' disease in children [3].

High impact information on CBLB

• To confirm the two-gene model, we produced a congenic strain carrying mutated Cblb alleles of the KDP rat on a non-KDP genetic background harboring the RT1(u) haplotype on its MHC [4].
• We have previously shown that two major susceptibility genes, the major histocompatibility complex (MHC) RT1(u) haplotype and Cblb (Casitas B-lineage lymphoma b) mutation, are responsible for the development of diabetes in KDP rats, suggesting a two-gene model for development of the disease [4].
• In these cells, CBLB constitutively binds the GRB2 adaptor predominantly through its N-terminal SH3 domain, to form a complex that is distinct from the GRB2.CBL and GRB2.SOS1 complexes [1].
• We have found that CBLB, a recently characterized molecule closely related to the CBL protooncogene product, is phosphorylated on tyrosine(s) following FL treatment of JEA2 human pro-B cells and THP1 monocytic cells [1].
• Treatment of JEA2 cells with interleukin (IL)-7 induces CBLB phosphorylation as well [1].

Biological context of CBLB

• To identify variants with possible effects on gene function as well as haplotype tagging polymorphisms, the human CBLB coding region was sequenced in 16 individuals with T1D: no variants predicted to change the amino-acid sequence were identified [5].
• CBLB was evaluated as a candidate gene for type 1 diabetes (T1D) susceptibility based on its association with autoimmunity in animal models and its role in T-cell costimulatory signaling [5].
• Seven single-nucleotide polymorphism (SNP) markers spanning the CBLB gene were genotyped in multiplex T1D families and assessed for disease association by transmission disequilibrium testing [5].
• The heterozygous region spans at least from D11Yok1 to Cblb on rat chromosome 11 [6].

Anatomical context of CBLB

• By positional cloning of the non-MHC major susceptibility locus lddm/kdp1, we recently identified a nonsense mutation in Cblb and also found that lymphocytes of KDP rats infiltrate into various tissues, indicating autoimmunity [6].

Other interactions of CBLB

• CBLB variants in type 1 diabetes and their genetic interaction with CTLA4 [2].

References