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

Gene Ontology (GO)

• Molecular function: protein kinase binding [GO:0019901]
• Cell component: membrane [GO:0016020]; cytosol [GO:0005829]
• Biological process: protein localization [GO:0008104]

Normal function

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.

Dysfunction and disease

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]