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LRBA
LPS responsive beige-like anchor protein
LRBA is located on the long (q) arm of chromosome 4, at band 4q31.3. Arm ratio per GRCh38 - banding schematic.
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Overview
LRBA (LPS responsive beige-like anchor protein) is a gene located on chromosome 4 that encodes a large intracellular protein critical for immune system function. The LRBA protein plays an essential role in maintaining the stability and surface expression of CTLA-4, an important negative regulator of T-cell activation. Loss-of-function variants in LRBA lead to immune dysregulation, manifesting as combined immunodeficiency with features of autoimmunity and inflammatory bowel disease. Because LRBA deficiency follows an autosomal recessive inheritance pattern, affected individuals inherit two pathogenic variants, one from each parent. The condition has been recognised within UK clinical genomics services, with LRBA included in multiple NHS Genomic Medicine Service panels for immunodeficiency and inflammatory conditions.
What the gene does
The LRBA protein functions primarily within the endosomal-lysosomal trafficking system, where it prevents premature degradation of the immune checkpoint molecule CTLA-4. By stabilising CTLA-4 and facilitating its recycling back to the cell surface, LRBA ensures appropriate down-regulation of immune responses after T-cell activation. This regulatory mechanism is essential for preventing excessive inflammation and maintaining immune tolerance to self-antigens. LRBA belongs to the BEACH domain-containing protein family, which are generally involved in vesicle trafficking, membrane dynamics, and organelle function. The protein is particularly abundant in B lymphocytes and T lymphocytes, where it influences cell survival, proliferation, and antibody production. Disruption of LRBA function results in accelerated CTLA-4 degradation, leading to unchecked T-cell activation, B-cell dysfunction, impaired antibody responses, and increased susceptibility to both infection and autoimmune disease.
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Chromosome location
LRBA is located on the long arm of chromosome 4 at position 4q31.3. The gene spans a substantial genomic region and encodes a very large protein of 2,863 amino acids. Its chromosomal position places it within a region that has been associated with immune-related phenotypes in genome-wide studies.
Protein structure
The LRBA protein is characterised by a modular architecture containing multiple functional domains distributed across its 2,863 amino acid length. A BEACH domain (amino acids 2200-2489) forms the protein's signature structural feature, typically involved in membrane trafficking and vesicle transport. Adjacent to this is a BEACH-type PH domain (amino acids 2073-2181), which may participate in membrane association and phospholipid binding. The C-terminal region contains a series of WD repeats: WD 1 (amino acids 1301-1343), WD 2 (amino acids 2591-2633), WD 3 (amino acids 2636-2679), WD 4 (amino acids 2695-2735), WD 5 (amino acids 2777-2816), and WD 6 (amino acids 2819-2858). These WD repeats likely form beta-propeller structures that mediate protein-protein interactions. A coiled coil region (amino acids 1006-1053) may facilitate oligomerisation or interaction with cytoskeletal elements. Multiple disordered regions are interspersed throughout the protein sequence, providing structural flexibility for its diverse cellular functions.
Key variants
Pathogenic variants in LRBA are distributed throughout the gene and include nonsense mutations, frameshift deletions and insertions, and splice-site alterations that typically result in loss of protein function. Because LRBA deficiency is inherited in an autosomal recessive manner, affected individuals carry biallelic pathogenic variants. The clinical severity can vary depending on the specific combination of variants and their effect on residual protein function.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1933C>T | p.Arg645Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency due to LRBA deficiency |
c.216+1G>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency due to LRBA deficiency |
c.2449C>T | p.Gln817Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency due to LRBA deficiency |
c.2836_2839del | p.Glu945_Glu946insTer | Pathogenic | ★★☆☆ | Combined immunodeficiency due to LRBA deficiency |
c.3985_3986del | p.Asp1329fs | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency due to LRBA deficiency |
c.4087C>T | p.Gln1363Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency due to LRBA deficiency |
c.5646-2A>T | - | Pathogenic | ★★☆☆ | Combined immunodeficiency due to LRBA deficiency |
c.7282C>T | p.Arg2428Ter | Pathogenic | ★★☆☆ | Combined immunodeficiency due to LRBA deficiency |
c.928C>T | p.Arg310Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency due to LRBA deficiency |
c.949C>T | p.Arg317Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Combined immunodeficiency due to LRBA deficiency |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in LRBA cause LRBA deficiency, a primary immunodeficiency disorder that typically presents in childhood with a constellation of immune-related features. Affected individuals experience recurrent respiratory and gastrointestinal infections due to impaired antibody production and B-cell dysfunction. Autoimmune manifestations are common and may include autoimmune cytopaenias, inflammatory bowel disease, type 1 diabetes, and autoimmune thyroid disease. Enteropathy with chronic diarrhoea is a frequent presenting feature. The condition represents a form of common variable immunodeficiency with additional autoimmune and inflammatory complications.
Inheritance pattern
Conditions caused by pathogenic LRBA variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
LRBA is included as a green-rated (high evidence) gene in several NHS Genomic Medicine Service panels. It appears in the Primary immunodeficiency or monogenic inflammatory bowel disease panel (R15), reflecting its role in immune dysregulation and gut inflammation. The gene is also listed in panels for Infantile enterocolitis & monogenic inflammatory bowel disease (green, R331), Intestinal failure or congenital diarrhoea (green, R331), Neonatal diabetes (green, R143), Multi-organ autoimmune diabetes, Familial diabetes, and Diabetes with additional phenotypes suggestive of a monogenic aetiology. Additional memberships include the DDG2P panel and COVID-19 research panel. This broad panel representation reflects the diverse clinical presentations associated with LRBA deficiency across immune, gastrointestinal, and metabolic domains.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is LRBA deficiency?
LRBA deficiency is an autosomal recessive immunodeficiency disorder caused by pathogenic variants in both copies of the LRBA gene. It typically presents with recurrent infections, autoimmune disease, and chronic diarrhoea, often beginning in childhood.
How is LRBA inherited?
LRBA deficiency follows autosomal recessive inheritance, meaning an affected individual must inherit one pathogenic variant from each parent. Parents who each carry one variant are typically unaffected but have a 25% chance with each pregnancy of having an affected child.
Why is LRBA included in diabetes gene panels?
LRBA deficiency can cause autoimmune destruction of insulin-producing pancreatic beta cells, leading to early-onset diabetes as part of a broader multi-organ autoimmune syndrome. This autoimmune diabetes phenotype has led to LRBA's inclusion in neonatal and familial diabetes panels within the NHS Genomic Medicine Service.