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LMBRD1
LMBR1 domain containing 1
The LMBRD1 gene encodes the LMBD1 protein, which is critical for transporting vitamin B12 out of lysosomes and plays a role in regulating insulin signalling. LMBRD1 provides instructions for the LMBD1 protein, which facilitates the transport of vitamin B12 (cobalamin) within cells, making it available for essential metabolic processes.
LMBRD1 is located on the long (q) arm of chromosome 6, at band 6q13. Arm ratio per GRCh38 - banding schematic.
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Overview
The LMBRD1 gene, also known by aliases such as cblF and LMBD1, encodes a protein involved in several crucial cellular functions. Its primary role involves the cellular metabolism of vitamin B12, a vital nutrient. The protein helps transport vitamin B12 from lysosomes, cellular compartments responsible for waste breakdown, for further processing into active forms.
Beyond vitamin B12 transport, the LMBRD1 gene product has also been observed to participate in the regulation of insulin signalling by influencing the removal of insulin receptors from the cell surface. Additionally, a specific isoform of the LMBD1 protein, sometimes called NESI, is thought to interact with components of the hepatitis D virus, potentially aiding in viral assembly.
What the gene does
The LMBD1 protein, produced from the LMBRD1 gene, has a multifaceted role in cellular physiology. A key function is its involvement in vitamin B12 (cobalamin) metabolism. Within the lysosomal membrane, LMBD1 interacts with another protein, ABCD4, to transport vitamin B12 out of lysosomes. This transport is essential for vitamin B12 to be converted into its active cofactor forms, adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl).
AdoCbl is a cofactor for methylmalonyl CoA mutase, an enzyme crucial for breaking down certain amino acids, fats, and cholesterol. MeCbl acts as a cofactor for methionine synthase, an enzyme that converts homocysteine to methionine, which the body uses for protein synthesis. Research also suggests that the LMBD1 protein is present in the cell's outer membrane, where it may be involved in removing the insulin receptor. This process is important for regulating insulin signalling and blood glucose levels. Furthermore, an isoform of LMBD1, known as NESI, has been observed to interact with components of the hepatitis D virus, potentially assisting in viral assembly.
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Chromosome location
The LMBRD1 gene is located on chromosome 6, specifically at band 6q13. This describes its precise position on the long (q) arm of chromosome 6. The gene spans a region of DNA that provides the instructions for synthesising the LMBD1 protein.
Protein structure
The LMBD1 protein is composed of 540 amino acids. It contains specific functional motifs crucial for its interactions and activity. These include a YERL motif, located at amino acids 232-235, which mediates interaction with adapter protein complex 2 and is essential for its function in clathrin-mediated endocytosis of the insulin receptor. Another key structural feature is the WTKF motif, found at amino acids 294-297, which also mediates interaction with adapter protein complex 2 and is vital for its role in clathrin-mediated endocytosis of the insulin receptor.
Key variants
Variants within the LMBRD1 gene can alter the function or production of the LMBD1 protein. These genetic changes can range from single base pair substitutions to larger deletions or insertions within the gene sequence. Pathogenic variants can lead to a non-functional or abnormally short protein, impacting its ability to perform critical cellular tasks, particularly those related to vitamin B12 metabolism.
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.1056del | p.Asn353fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.1339-1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria and homocystinuria type cblF |
c.399del | p.Lys133fs | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria and homocystinuria type cblF |
c.515_516del | p.Thr172fs | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria and homocystinuria type cblF |
c.967_970del | p.Leu323fs | Pathogenic/Likely pathogenic | ★★☆☆ | Methylmalonic aciduria and homocystinuria type cblF |
g.69697707_69697708insTATCAGATTATCAGAAGTTATATTAGTCTGAAAGATAAAAATACAGTTAAAATATAAAAACCGCATTAATAAATACATTTGGATTTAAAAAGT | - | Pathogenic | ★☆☆☆ | Methylmalonic aciduria and homocystinuria type cblF |
c.1067del | p.Leu356fs | Pathogenic | ★☆☆☆ | Methylmalonic aciduria and homocystinuria type cblF |
c.317_318del | p.Ser106fs | Pathogenic | ★☆☆☆ | Methylmalonic aciduria and homocystinuria type cblF |
c.690del | p.Ala231fs | Pathogenic | ★☆☆☆ | Methylmalonic aciduria and homocystinuria type cblF |
c.916-1G>T | - | Pathogenic | ★☆☆☆ | Methylmalonic aciduria and homocystinuria type cblF |
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
Pathogenic variants in the LMBRD1 gene are known to cause methylmalonic acidaemia with homocystinuria, cblF type. This is a rare inherited metabolic disorder characterised by developmental delay, neurological problems, eye defects, and blood abnormalities. The underlying mechanism involves the inability of the altered LMBD1 protein to properly process vitamin B12, leading to the accumulation of harmful substances in the body.
No disease links recorded for this gene in our reference set.
UK clinical status
The LMBRD1 gene is included in several expert-curated panels within the NHS Genomic Medicine Service's PanelApp. It is listed with a 'green' rating on the Developmental Disorders Gene - Rerun (DDG2P) panel, the Foetal anomalies panel (R21), the Likely inborn error of metabolism panel (R98), and the Undiagnosed metabolic disorders panel. A 'green' rating indicates that there is strong evidence for the gene's association with the conditions covered by these panels.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the LMBRD1 gene?
The LMBRD1 gene provides instructions for the LMBD1 protein, which is primarily involved in transporting vitamin B12 (cobalamin) out of lysosomes, making it available for conversion into active forms essential for metabolic processes.
What health condition is associated with LMBRD1 gene variants?
Variants in the LMBRD1 gene are known to cause methylmalonic acidaemia with homocystinuria, cblF type. This is a metabolic disorder affecting development, neurological function, and other bodily systems.
How does the LMBD1 protein relate to insulin?
Research suggests that the LMBD1 protein, in addition to its role in vitamin B12 transport, is involved in regulating insulin signalling. It appears to participate in removing the insulin receptor from the cell membrane, which helps control blood glucose levels.
References
- Deme JC, Hancock MA, Xia X. Purification and interaction analyses of two human lysosomal vitamin B12 transporters: LMBD1 and ABCD4. Molecular membrane biology. 2014. PMID: 25535791
- Huang C, Jiang JY, Chang SC. Nuclear export signal-interacting protein forms complexes with lamin A/C-Nups to mediate the CRM1-independent nuclear export of large hepatitis delta antigen. Journal of virology. 2013. PMID: 23175358
- Tseng LT, Lin CL, Tzen KY. LMBD1 protein serves as a specific adaptor for insulin receptor internalization. The Journal of biological chemistry. 2013. PMID: 24078630
- Rutsch F, Gailus S, Suormala T. LMBRD1: the gene for the cblF defect of vitamin B₁₂ metabolism. Journal of inherited metabolic disease. 2011. PMID: 20446115