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LMBRD1
LMBR1 domain containing 1
The LMBRD1 gene provides instructions for a protein critical in vitamin B12 metabolism and transport, with implications for energy production and neurological function. LMBRD1 encodes the LMBD1 protein, which plays a key role in processing and transporting vitamin B12 within cells.
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, or LMBR1 domain containing 1, is crucial for cellular metabolism, primarily through its involvement in vitamin B12 (cobalamin) processing. The protein produced from this gene, LMBD1, facilitates the conversion of vitamin B12 into its active coenzyme forms: adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl).
These active forms are essential cofactors for enzymes involved in critical metabolic pathways, such as the breakdown of certain amino acids and fats, and the conversion of homocysteine to methionine. Deficiencies in these pathways due to LMBRD1 variants can lead to a build-up of harmful substances in the body.
What the gene does
The LMBD1 protein, encoded by the LMBRD1 gene, plays a dual role in vitamin B12 metabolism. It is located in the membrane of lysosomes, cellular organelles responsible for waste breakdown and recycling. Here, LMBD1 works in conjunction with the ABCD4 protein to transport vitamin B12 out of lysosomes, making it available for conversion into its active forms, AdoCbl and MeCbl.
AdoCbl is a vital cofactor for methylmalonyl CoA mutase, an enzyme that aids in breaking down specific amino acids, fats, and cholesterol. MeCbl acts as a cofactor for methionine synthase, an enzyme necessary for converting homocysteine into methionine, an amino acid crucial for protein synthesis and other cellular compounds. Research also indicates LMBD1's presence in the plasma membrane, where it may contribute to regulating insulin signalling by facilitating the removal of the insulin receptor from the cell surface. Additionally, an isoform of the LMBD1 protein, sometimes referred to as NESI, is thought to interact with the hepatitis D virus, potentially assisting in viral assembly.
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Chromosome location
The LMBRD1 gene is situated on chromosome 6 at position 6q13. This specific location on the long arm of chromosome 6 contains the genetic instructions for producing the LMBD1 protein, which is 540 amino acids in length.
Protein structure
The LMBD1 protein, composed of 540 amino acids, contains specific motifs critical for its function. These include a YERL motif, located at amino acids 232-235, and a WTKF motif, found at amino acids 294-297. Both motifs are involved in mediating interactions with adapter protein complex 2, which is essential for the protein's role in the clathrin-mediated endocytosis of the insulin receptor.
Key variants
Variants within the LMBRD1 gene can impact the structure and function of the LMBD1 protein. Pathogenic variants can disrupt the protein's ability to properly process and transport vitamin B12, leading to metabolic dysregulation. These genetic changes can result in the production of an abnormally short or non-functional protein.
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 | ★★☆☆ | LMBRD1-related disorder |
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
Variants in the LMBRD1 gene are associated with inherited metabolic conditions. One such condition is methylmalonic acidaemia with homocystinuria, cblF type. Individuals affected by this disorder may experience developmental delay, eye defects, neurological problems, and blood abnormalities due to the impaired metabolism of vitamin B12.
No disease links recorded for this gene in our reference set.
UK clinical status
The LMBRD1 gene is recognised in the UK by NHS England's Genomic Medicine Service, featuring on several national testing panels. It is listed on the Diagnostic GMS Paediatric (green) panel for developmental disorders (DDG2P), the Foetal anomalies (green, R21) panel, and both the Likely inborn error of metabolism (green, R98) and Undiagnosed metabolic disorders (green) panels.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the LMBRD1 gene?
The LMBRD1 gene primarily codes for a protein called LMBD1, which is crucial for processing and transporting vitamin B12 within cellular lysosomes. This allows vitamin B12 to be converted into its active forms, essential for various metabolic pathways.
How do LMBRD1 gene variants affect health?
Variants in the LMBRD1 gene can lead to metabolic disorders, such as methylmalonic acidaemia with homocystinuria, cblF type. These conditions arise when the LMBD1 protein cannot properly handle vitamin B12, leading to an accumulation of harmful substances and affecting neurological and developmental functions.
Where is the LMBD1 protein found in the cell?
The LMBD1 protein is mainly found in the membrane of lysosomes, where it helps transport vitamin B12. It may also be present in the plasma membrane, potentially influencing insulin signalling, and an isoform of the protein interacts with the hepatitis D virus.
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