Alt. symbols: CDC4L | BGL | LAB300 | LBA

Approved name: LPS responsive beige-like anchor protein
Alt. names: LPS-responsive vesicle trafficking, beach and anchor containing

Location: 4q31.3: 150264435 - 151015727 (-)
Gene type: protein_coding, 23 transcripts.

Scores: LoFtool: 0.749000 | pLI: 0.04422944 | LOEUF: 0.417

HGNC: 1742

NCBI: 987, RefSeq: NG_032855.1

Ensembl: ENSG00000198589.15

LRG_1324 | Status: public

OMIM: 606453

Expression | ProteinAtlas

LRBA encodes a member of the BEACH-WD40 protein family whose expression is induced in B cells and macrophages by bacterial lipopolysaccharides (LPS). LRBA associates with protein kinase A and may be involved in leading intracellular vesicles to activated receptor complexes, which aids in the secretion and/or membrane deposition of immune effector molecules. LRBA facilitates the recycling of CTLA4-containing vesicles in regulatory T cells, thereby controlling T-cell driven immune responses.

Biallelic missense, nonsense, frameshift and splice site mutations, as well as copy number changes, in LRBA have been associated with autosomal recessive CVID type 8 [OMIM:614700] in at least 139 patients, many of whom were identified in large cohorts of patients with CVID, PAD, ALPS, or autoimmunity by NGS (PMID: 26122175, 27379089, 29867916, 30363934, 31432443, 31942606, 33425813, 34975878). Affected individuals tend to have early onset, recurrent sinopulmonary infections and a broad spectrum of immune dysregulatory phenotypes such as cytopenias, pulmonary and GI disease (PMID: 26707784, 26768763, 27146671, 27888588, 28512785, 28884992, 31871423, 32154999, 32284663, 32506362, 32615565, 33774840). Autoimmune thyroid disease, hepatosplenomegaly or other signs of lymphoproliferation, atopies, and infiltrative CNS disease may also be present (PMID: 31857261). Some patients may also present with HLH or an ALPS-like phenotype (PMID: 31432443, 34120644). Most patients show low Treg, switched memory B cell and plasmablast levels, while more variable immunologic findings include hypogammaglobulinemia, impaired vaccine responses, or abnormalities in B, T or NK cell counts. Lopez-Herrera et al. (2012) identified the first 4 LRBA mutations in 5 CVID patients (PMID: 22608502), with one point mutation likely destabilizing the protein, while 3 others led to absent protein expression. All patients showed reduced switched memory B-cells levels, and LRBA-deficient B cells cultured under conditions favoring CSR and plasmablast development failed to proliferate, differentiate into antibody-secreting cells, or induce plasmablast markers, while LRBA-deficient EBV cells showed increased susceptibility to apoptosis. Moreover, the abnormal accumulation of organelles in B cells and low colocalization of LC3 with lysosomes suggested that this increased susceptibility to apoptosis might be a consequence of defective LRBA-mediated autophagy. This hypothesis is consistent with prior data showing showing that LRBA colocalizes with lysosomes, the trans-Golgi network, the ER, the perinuclear ER, and endocytic vacuoles - all organelles that have been linked to autophagosomal metabolism (PMID: 11254716). Shortly thereafter, Alangari et al. (2012) identified a null LRBA mutation in 5 members of a large consanguineous family who all had early-onset IBD, though some had CID- or CVID-like features while others showed normal Ig levels, vaccine titers, T- and B-cell numbers, and proliferative responses (PMID: 22721650). Burns et al. (2012) then described a patient presenting with multiple autoimmune manifestations, elevated IgG levels, normal vaccine responses, and normal T cell populations and function who developed CVID secondary to rituximab treatment (PMID: 22981790). Lo et al. (2015) found a dramatic response of LRBA-deficient patients to abatacept, a CTLA4-Ig fusion drug, suggesting its potential regulation of CTLA-4 (PMID: 26206937). The authors supported this hypothesis by showing that LRBA colocalized with CTLA-4 in endosomal vesicles, that LRBA LOF increased CTLA-4 turnover and levels in FoxP3+ Tregs and activated Th cells, and that chloroquine-mediated inhibition of lysosome degradation prevented CTLA-4 loss in LRBA-deficient cells. Moreover, as LRBA deficiency leads to functional CTLA-4 loss, patients with the former would also be expected to show abnormalities on transendocytosis assay as well (PMID: 28159733). [Load More]