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LMBRD1 gene

LMBR1 domain containing 1
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Normal Function

The LMBRD1 gene provides instructions for making a protein, called LMBD1, that is involved in the conversion of vitamin B12 (also known as cobalamin) into one of two molecules, adenosylcobalamin (AdoCbl) or methylcobalamin (MeCbl). AdoCbl is required for the normal function of an enzyme known as methylmalonyl CoA mutase. This enzyme helps break down certain protein building blocks (amino acids), fats (lipids), and cholesterol. AdoCbl is called a cofactor because it helps methylmalonyl CoA mutase carry out its function. MeCbl is also a cofactor, but for an enzyme known as methionine synthase. This enzyme converts the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds.

The LMBD1 protein is found in the membrane that surrounds cell structures called lysosomes. Lysosomes are compartments within cells in which enzymes digest and recycle materials. In the lysosomal membrane, the LMBD1 protein interacts with another protein called ABCD4 (produced from the ABCD4 gene). Together, these two proteins transport vitamin B12 out of lysosomes, making it available for further processing into AdoCbl and MeCbl.

Studies suggest that the LMBD1 protein is also found in the membrane that surrounds the cell (the plasma membrane). Here, the protein appears to be involved in removing another protein called the insulin receptor from the membrane. Removal of this receptor helps regulate insulin signaling, which controls blood sugar levels in the body.

Another version (isoform) of the LMBD1 protein, sometimes called NESI, can also be produced from the LMBRD1 gene. This protein interacts with a region called the nuclear export signal (NES) of a protein that forms a piece of the hepatitis D virus. It is thought that interaction with NESI aids in the assembly of the virus. The hepatitis D virus can cause liver disease, although infection is rare and requires co-infection with a related virus called hepatitis B.

Health Conditions Related to Genetic Changes

Methylmalonic acidemia with homocystinuria

At least nine mutations in the LMBRD1 gene have been found to cause methylmalonic acidemia with homocystinuria, cblF type, one form of a disorder that causes developmental delay, eye defects, neurological problems, and blood abnormalities. LMBRD1 gene mutations involved in this condition lead to production of an abnormally short LMBD1 protein that is unable to function. A shortage of functional LMBD1 protein prevents the release of vitamin B12 from lysosomes, so the vitamin is unavailable for the production of AdoCbl and MeCbl. Because both of these cofactors are missing, the enzymes that require them (methylmalonyl CoA mutase and methionine synthase) do not function normally. As a result, certain amino acids, lipids, and cholesterol are not broken down and homocysteine cannot be converted to methionine. This dual defect results in a buildup of toxic compounds as well as homocysteine, and a decrease in the production of methionine within the body. This combination of imbalances leads to the signs and symptoms of methylmalonic acidemia with homocystinuria.

More About This Health Condition

Other Names for This Gene

  • bA810I22.1
  • C6orf209
  • cblF
  • FLJ11240
  • HDAg-L-interacting protein NESI
  • hepatitis delta antigen-L interacting protein
  • liver regeneration p-53 related protein
  • LMBD1
  • MAHCF
  • NESI
  • nuclear export signal-interacting protein
  • probable lysosomal cobalamin transporter

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Research Resources

References

  • Deme JC, Hancock MA, Xia X, Shintre CA, Plesa M, Kim JC, Carpenter EP, Rosenblatt DS, Coulton JW. Purification and interaction analyses of two human lysosomal vitamin B12 transporters: LMBD1 and ABCD4. Mol Membr Biol. 2014 Nov-Dec;31(7-8):250-61. doi: 10.3109/09687688.2014.990998. Citation on PubMed
  • Huang C, Jiang JY, Chang SC, Tsay YG, Chen MR, Chang MF. Nuclear export signal-interacting protein forms complexes with lamin A/C-Nups to mediate the CRM1-independent nuclear export of large hepatitis delta antigen. J Virol. 2013 Feb;87(3):1596-604. doi: 10.1128/JVI.02357-12. Epub 2012 Nov 21. Citation on PubMed or Free article on PubMed Central
  • Rutsch F, Gailus S, Suormala T, Fowler B. LMBRD1: the gene for the cblF defect of vitamin B₁₂ metabolism. J Inherit Metab Dis. 2011 Feb;34(1):121-6. doi: 10.1007/s10545-010-9083-9. Epub 2010 May 6. Review. Citation on PubMed
  • Tseng LT, Lin CL, Tzen KY, Chang SC, Chang MF. LMBD1 protein serves as a specific adaptor for insulin receptor internalization. J Biol Chem. 2013 Nov 8;288(45):32424-32. doi: 10.1074/jbc.M113.479527. Epub 2013 Sep 27. Citation on PubMed or Free article on PubMed Central
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